Therapeutic composition and methods

ABSTRACT

In exemplary embodiments, the disclosure provides a Colesevelam Colon Specific Drug Delivery System for use in treatment of, for example, cholestasis and/or cholestatic pruritus.

This application is a continuation in part of U.S. Ser. No. 16/537,823filed Aug. 12, 2019, which claims benefit under 35 USC § 119(e) to U.S.Ser. No. 62/718,055 filed Aug. 13, 2018; to U.S. Ser. No. 62/736,715filed Sep. 26, 2018; and to U.S. Ser. No. 62/804,312 filed Feb. 12,2019, the entireties of which are incorporated by reference herein.

SPECIFICATION Background

Bile acids, steroid acids that are found predominantly in the bile ofmammals, regulate cholesterol, triglyceride, glucose and energyhomeostasis, and facilitate digestion and absorption of lipids in thesmall intestine. Emulsification of lipids and fat-soluble vitamins inthe intestine allows the formation of micelles that can then betransported via the lacteal system. Other functions of bile acidsinclude driving the flow of bile to eliminate catabolites from the liverand aiding in the reduction of the bacteria flora found in the smallintestine and biliary tract. Bile acids are also involved in theregulation of their own synthesis and enterohepatic circulation. See,e.g., Staels et al., Diabetes Care (2009) vol. 32 no. suppl 2 S237-S245.

In humans, bile acid production occurs primarily in the perivenoushepatocytes through a series of enzymatic reactions that convertcholesterol into the two primary bile acids, cholic acid andchenodeoxycholic acid. The primary bile acids are synthesized by twodistinct pathways. In the “classic” or “neutral” pathway, the primarybile acids are produced by hydroxylation of cholesterol throughcatalysis by the cytochrome P450 enzyme cholesterol 7alpha-hydroxylase(cyp7a1), which catalyzes the first and rate-limiting step in theclassical bile acid synthesis pathway. (See, e.g., Inagaki et al., CellMetabolism 2:217-25 (October 2005)).

Bile acids synthesized in the liver are immediately secreted into bile,reabsorbed in the intestine and transported back to the liver. Theenterohepatic circulation of bile acids is very efficient in humans.Small amounts of bile acids may spill over into the systemiccirculation, reabsorbed when passing through the renal tubules in thekidney, and are then circulated back to the liver through systemiccirculation. Some bile acids secreted in the bile duct are reabsorbed inthe cholangiocytes (bile duct epithelial cells) and recycled back tohepatocytes (the cholangiohepatic shunt). Bile acids are stored in thegallbladder. After each meal, cholecystokinin secreted from theintestine stimulates gallbladder contraction to empty bile acids intothe intestinal tract. When passing down the intestinal tract, smallamounts of unconjugated bile acids are reabsorbed in the upper intestineby passive diffusion. Most bile acids (95%) are reabsorbed in the brushborder membrane of the terminal ileum, transdiffused across theenterocyte to the basolateral membrane, and secreted into portal bloodcirculation to liver sinusoids and are taken up into hepatocytes. DCA isreabsorbed in the colon and recycled with CA and CDCA to the liver. Abile acid pool of ˜3 g consisting of ˜40% CA, 40% CDCA, 20% DCA, andtrace amount of LCA, is recycled 4 to 12 times a day. Bile acids lost inthe feces (˜0.5 g/day) are replenished by de novo synthesis in the liverto maintain a constant bile acid pool. (See Chiang J Y. Bile acidmetabolism and signaling. Compr. Physiol. 2013 July; 3(3):1191-212).

When cholic acid and chenodeoxycholic acid are secreted into the lumenof the intestine, intestinal bacteria dehydroxylate a portion of each toform the secondary bile acids, deoxycholic acid (derived from cholicacid) and lithocholic acid (derived from chenodeoxycholic acid). Hepaticcells may conjugate these four bile with one of two amino acids, glycineor taurine, to form a total of eight possible conjugated bile acids,referred to as bile salts. Thus, in total the principal bile acids arecholic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid,deoxycholic acid and lithocholic acid. All four of these bile acids canbe transported back into the blood stream, be returned to the liver, andbe re-secreted through enterohepatic circulation. (See, e.g., Staels etal., Diabetes Care (2009) vol. 32 suppl 2 S237-S245).

The primary bile acids (cholic acid and chenodeoxycholic acid) aresynthesized in the liver), while the secondary bile acids (deoxycholicacid and lithocholic acid) are made by bacteria. The four bile acids aresecreted into the bile canalicular lumen for storage in the gallbladderas mixed micelles with phospholipids and cholesterol. Upon ingestion ofa meal, cholecystokinin stimulates gallbladder contraction resulting inits release of micellar bile acids into the intestinal lumen to aiddigestion. Enterohepatic circulation enables about 90-95% of bile acidsto be reabsorbed from the distal ileum and transported back to theliver; this bile acid uptake and transportation occurs primarily bypericentral hepatocytes. The approximately 5% of bile acids that are notreabsorbed are eliminated in the feces, and that amount of loss issubsequently replaced by de novo bile acid synthesis in the liver. See,e.g., Rose et al., Cell Metabolism, 14:1, pp 123-130 (6 Jul. 2011).

As described herein, abnormal bile acid homeostasis can result in, orexacerbate, a number of disorders, including cholestasis, portosystemicshunt, Crohn's disease, hepatic microvascular dysplasia, inflammatorybowel diseases (IBD), irritable bowel syndrome, colonic cancer,cholestasis, cholestatic pruritus, insufficient control of bloodglucose, and cardiovascular disease, such as hypercholesterolemia. Inaddition, bile acids play a role in modulating the metabolic syndrome, acluster of cardiovascular disease risk factors that include visceralobesity, insulin resistance, dyslipidemia, increased blood pressure, andhypercoagulability. Thus, modulation of bile acid activity can provide anumber of beneficial therapeutic effects. Current approaches to diseasemanagement include: Low fat diet, oral bile acid binders(cholestyramine, colestipol, colesevelam), Cholestyramine treatment isby far the most studied of the existing agents, Colesevelam binds bileacids with a higher affinity than cholestyramine or colestipol; onestudy found it to be effective in patients who had failed treatment withcholestyramine.

The major goal of any drug delivery system is to supply a therapeuticamount of drug to a target site in a body, so that the desired drugconcentration can be achieved swiftly and then maintained. Targeted drugdelivery implies selective and effective localization of drug into thetarget at therapeutic concentrations with limited access to non-targetsites. A targeted drug delivery system is preferred in drugs havinginstability, low solubility and short half-life, large volume ofdistribution, poor absorption, low specificity and low therapeuticindex. Targeted drug delivery may provide maximum therapeutic activityby preventing degradation or inactivation of drug during transit to thetarget site. Meanwhile, it can also minimize adverse effects because ofinappropriate disposition and minimize toxicity of potent drugs byreducing dose. An ideal targeted delivery system should be nontoxic,biocompatible, and biodegradable and physicochemically stable in vivoand in vitro. The preparation of the delivery system must be reasonablysimple, reproducible and cost-effective. The targeted drug delivery isdependent on the identification and exploitation of a attribute that isspecific to the target organ. A Colon Specific Drug Delivery System(CSDDS) is beneficial for the localized treatment of several diseases,for example, mainly inflammatory bowel diseases (IBD), irritable bowelsyndrome, colonic cancer, cholestasis, cholestatic pruritus,insufficient control of blood glucose, and cardiovascular disease, suchas hypercholesterolemia. An aim of the invention is to achieve aclinically CSDDS relevant bioavailability of poorly absorbed drugs fromthe upper parts of the gastrointestinal tract because of their polarnature and/or vulnerability to chemical and enzymatic degradation in thesmall intestine specifically for proteins and peptides. The colonic drugdelivery provide more effective therapy of diseases such as, forexample, inflammatory bowel diseases (IBD), irritable bowel syndrome,colonic cancer, cholestasis, cholestatic pruritus, insufficient controlof blood glucose, and cardiovascular disease, such ashypercholesterolemia, and also has potential to deliver macromoleculardrugs orally. Colon related pathologies range in seriousness fromconstipation and diarrhea to the incapacitating inflammatory boweldiseases through to colon cancer, the third most widespread form ofcancer in both women and men.

Lipids constitute a broad group of naturally occurring hydrophobic oramphiphilic molecules that include fatty acids, glycerolipids,glycerophospholipids, sphingolipids, saccharolipids, and polyketides,sterol lipids and prenol lipids. The main biological functions of lipidsinclude energy storage, as structural components of cell membranes, andas important signaling molecules. Given these fundamental roles, allcells use and rely on lipids. One process used to transport lipids tocells involves apolipoproteins. Apolipoproteins are proteins that bindto lipids to form lipoproteins, which are the vehicles used fortransporting the lipids, including triglycerides and cholesterol,through the lymphatic and circulatory systems. The lipid components oflipoproteins are not themselves soluble in water. However, because oftheir amphipathic properties, apolipoproteins and other amphipathicmolecules (such as, e.g., phospholipids) can surround the lipids,creating the lipoprotein particle that is itself water-soluble, and canthus be carried through water-based circulation, i.e., blood and lymph,etc.

There five major groups of lipoprotein particles, and the lipoproteindensity and type of apolipoproteins it contains determines the fate ofthe particle and its influence on metabolism. Chylomicrons are thelargest lipoprotein particle and these particles carry triglyceridesfrom the intestines to the liver, skeletal muscle, and adipose tissue.Very low-density lipoprotein (VLDL) particles are large,triglyceride-rich lipoprotein secreted by the liver that transportstriglycerides to adipose tissue and muscle. The third group lipoproteinparticles are intermediate-density lipoprotein (IDL) particles, anintermediate between VLDL and low-density lipoprotein (LDL). IDLparticles are formed when lipoprotein lipase removes triglycerides fromVLDL particles in the capillaries and the return these smaller particlesto the circulation. The IDL particles have lost most of theirtriglyceride, but they retain cholesteryl esters. Some of the IDLparticles are rapidly taken up by the liver; others remain incirculation, where they undergo further triglyceride hydrolysis and areconverted to LDL. LDL particles carry cholesterol from the liver tocells of the body, where these particles bind to LDL receptors that aresubsequently endocytosed in vesicles form via clathrin-coated pits.After the clathrin coat is shed, the vesicles ultimately deliver the LDLto lysosomes where the cholesterol esters are hydrolyzed. The last groupof lipoprotein particles is high-density lipoprotein (HDL) particles,which collect cholesterol from the body's tissues and bring it back tothe liver.

High levels of lipids, e.g., cholesterol, and/or lipoprotein particles,e.g., VLDL, IDL, and/or LDL can have deleterious effects on thecardiovascular system. For example, as a major extracellular carrier ofcholesterol, LDL plays important physiologic roles in cellular functionand regulation of metabolic pathways. Cells have complex feedbackmechanisms that ensure sufficient supply of cholesterol and prevent itsexcessive accumulation in the blood. However, under pathologicconditions of, e.g., hyperlipidemia, oxidative stress and/or geneticdisorders, specific components of LDL become oxidized or otherwisemodified, with a consequence that cholesterol transport by such modifiedLDL is diverted from its physiologic targets and accumulates in theblood.

One effect of this accumulation is the high amounts of cholesteroland/or LDL become embedded in the walls of blood vessels, an in so doinginvokes an inflammatory response. In response to this inflammation,blood monocytes adhere to the endothelium, transmigrate into thesubendothelial space, and differentiate toward macrophages. Macrophages,in turn, engulf the cholesterol deposits and modified LDL byphagocytosis via scavenger receptors, which are distinct from LDLreceptors. However, the adaptive mechanisms mediated by macrophages arenot sufficient to process the uncontrolled cholesterol and/or LDLdeposition seen under pathologic conditions. As a result, thelipid-laden macrophages transform into “foam cells” or “foamy cells”having a M1 phenotype. Both cholesterol/LDL deposition and the attendantfoam cell-mediated pro-inflammatory reactions in the blood wall lead tothe development of atherosclerotic lesions. Left untreated, this lipidaccumulation and pro-inflammatory response result in the progression ofthe lesions, which eventually leads to a cardiovascular disease.

Another effect of high cholesterol/LDL accumulation in the blood is theformation LDL aggregates or LDL agglomerates. Being of high molecularweight, LDL agglomerates initiate an inflammatory response in a mannersimilar to that invoked by pathogens like viruses or bacteria. Theinflammatory response triggers agglomerate uptake by macrophages whichconverts these cells into foam cells having a M1 phenotype, and therelease of inflammation inducing molecules. Once again, left untreated,the lipid accumulation and pro-inflammatory response can result in acardiovascular disease.

Other drugs are known to lower serum concentrations of LDL cholesteroland may help prevent formation, slow progression, and cause regressionof atherosclerotic lesions. Further, trials of these lipid-regulatingdrugs have shown an association between increases in HDL cholesterol andreduction in clinical coronary events. For example, HMG-CoA reductaseinhibitors, otherwise known as “statins,” inhibit the enzyme thatcatalyzes the rate-limiting step in cholesterol syntesis. Statins aremore effective than other drugs in lowering plasma concentrations of LDLcholesterol, increasing HDL cholesterol by up to about 15% with highdoses, and reducing levels of triglyceride. Statins lower LDLcholesterol levels in the bloodstream by indirectly increasing thenumber of LDL receptors on the surface of cells. Despite the success ofstatins, there is a significant patient population, particularly thoseindividuals having substantially elevated blood cholesterol levels, forwhich these drugs alone are insufficient to achieve the desiredefficacy. Moreover, because statins are not able to mobilize cholesterolsequestered in tissue and/or cells (e.g., foam cells in atheroscleroticplaques), this class of compounds, alone, cannot prevent the developmentof atherosclerosis.

Bile acid sequestrants are another lipid regulating drug that may lowerLDL-cholesterol by about 10 to 20 percent. Cholestyramine, colestipol,and colesevelam are the three main bile acid sequestrants currentlyavailable. Small doses of sequestrants can produce useful reductions inLDL-cholesterol. These drugs also tend to increase HDL cholesterol and,in patients with hypertriglyceridemia, cholestyramine, colestipol and,to a lesser extent, colesevelam raise plasma triglycerides. When thesedrugs are combined, their effects are added together to lowerLDL-cholesterol by over 40 percent.

Attempts to treat cardiovascular disease by controlling levels of lipidsand/or lipoproteins in the blood have met with limited success. Forexample, although administration of statins reduces cardiovascular riskin some individuals, these therapeutic compounds do not reducetriglyceride levels. Thus, in individuals at cardiovascular risk whoexhibit deleteriously high levels of triglycerides, another class oftherapeutic compounds called fibrates may be administered. However,although lowering triglyceride and LDL levels, fibrates do not affectthe level of HDL, the lipoprotein particle known to be protectiveagainst cardiovascular disease. Lastly, combination treatments involvingstatins and fibrates, while effective, cause a significant increase tothe risk of myopathy and rhabdomyolysis, and therefore can only becarried out under very close medical supervision. In view of theseproblems, there is, therefore, clearly a need for improved compounds andcompositions for the use and treatment of cardiovascular diseases,including those associated with high lipid and/or lipoprotein levels.The present specification discloses pharmaceutical compositions andmethods for treating an individual suffering from a cardiovasculardisease.

Diabetes mellitus refers to a group of metabolic diseases in whichpatients have high blood sugar level. It is a major public healthproblem due to high number of affected patients since 171 million peopleworldwide corresponding to 2.8% of the population in 2000 are diabetic.Diabetes is now considered as epidemic: the number of patients shouldalmost double by 2030. There are mainly two types of diabetes. Type 1diabetes is mainly characterized by insulin dependent patients, is knownto be autoimmune, sometimes triggered by infection factors. It usuallystarts in patients younger than 30 and it accounts about 5-10% of allcases of diabetes. Type 2 diabetes, mainly characterized by insulinindependence, has a later onset than type 1 diabetes and is thereforenamed adult-onset diabetes. It accounts for about 90-95% of all diabetescases. Many factors can potentially give rise to, or exacerbate type 2diabetes. These include hypertension, elevated cholesterol, metabolicsyndrome and overweight/obesity. As an example, approximately 90% ofpatients with type 2 diabetes are overweight/obese. Other forms ofdiabetes include gestational diabetes, congenital diabetes, cysticfibrosis-related diabetes, steroid diabetes, and several forms ofmonogenic diabetes. Current treatments consist in insulin administrationfor type 1 diabetes and/or glucose-lowering medications or insulinsensitizers for type 2 diabetes. Insulin is a hormone involved in theglucose homeostasis, together with glucagon. In response to risinglevels of blood glucose, insulin is produced by pancreatic beta cellslocated in the islets of Langerhans. Thus, glucose is taken up from theblood by hepatocytes, muscle cells, and adipocytes used either as energysource or for storage as glycogen and triglycerides. It also inhibitslipolysis, preventing fatty acid release from fat tissues. On thecontrary, low blood glucose levels result both in a reduced productionand release of insulin. Together with glucagon action, it results inglucose release into blood stream. In pathological situations, eitherinsulin production by beta-cells is not sufficient (type 1 diabetes)and/or cells poorly respond to it (insulin resistance; type 2 diabetes),leading to persistent high levels of blood glucose. Precise mechanismsinvolved in these pathologies are not yet completely understood.

Decrease in insulin production characterizing type 1 diabetes is due toa destruction of beta-cells by an autoimmune process that consists inautoantibodies production, activation of self-reactive lymphocytes andinfiltration of pancreas to destroy beta-cells. Type 2 diabetes mellitusis considered as a complex metabolic disorder. It results from thecombination of impaired pancreatic insulin secretion due to beta-cellsdysfunction, insulin resistance as well as damaged glucagon secretionImpairment of glucose-stimulated production of insulin involvesprogressive loss of pancreatic beta-cells as well as a decline in isletcells function. Insulin resistance consists for example in suppressed orreduced effects of insulin in peripheral organs/tissues (liver, musclesand fat tissues) or enhanced lipolysis in adipocytes leading toincreased circulation of free fatty acids. Those events result inincreased endogenous glucose production by the liver together withdecreased glucose uptake due to reduced insulin receptor expression,defects in post-receptor actions of insulin, hepatic glucoseoverproduction or blocking of insulin-signaling pathways. Insulinresistance is a hallmark of a more complex syndrome, named metabolicsyndrome that is a grouping of risk factors for coronary heart diseaseand diabetes mellitus including abdominal obesity, elevated triglyceridelevels, decreased high-density lipoprotein levels, elevated bloodpressure, and elevated fasting plasma glucose levels. 75% of type 2diabetes patients have metabolic syndrome.

Persistent high blood glucose leads both to acute and chroniccomplications that may be very disabling, even fatal for diabeticpatients such as heart disease and stroke that are the mostlife-threatening consequences of diabetes mellitus. Long-term persistentelevated blood glucose damages blood vessels, leading to microvascularand macrovascular angiopathy which account for most of the increasedmorbidity and mortality associated with the disease. Microvascularcomplications are responsible of diabetic cardiomyopathy, nephropathyboth sometimes leading to organ failure, retinopathy which can lead tosevere vision loss and neuropathy. Macrovascular complications ratherconcerns cardiovascular impairments that are responsible of coronaryartery disease that in the end provokes angina or myocardial infarction,diabetic myonecrosis, peripheral vascular disease and stroke.Macrovascular complications are more common and up to 80% of patientswith type 2 diabetes will develop or die of a macrovascular disease.

Unfortunately, existing treatments do not succeed in restoringnormoglycaemia in the long term, since beta-cell function declines overtime. Moreover, there is presently no single drug able to reverse allaspects of the disease.

Control of glycaemia in type 1 diabetes is almost exclusively achievedwith injections of exogenous insulin, since patients no longer produceinsulin. Insulin may also be administered in type 2 diabetes patients,when glucose-lowering drugs and diet fail to control glycaemia. It isnowadays more frequently administered to these patients, since it delaysdevelopment and progression of complications. Use of insulin, however,comprises side effects including hypoglycaemia when dosage is notappropriate, increased risk of developing colorectal cancer and gainingweight, which is not recommended for diabetic patients, particularlyobese ones.

The progressive nature of type 2 diabetes implies that many patientswill eventually require a combination of antidiabetics, possiblytogether with insulin. Antidiabetics have been developed in order tocounteract the main mechanisms involved in type 2 diabetes: insulinresistance (biguanides and thiazolidinediones) and insulin secretion(sulfonylureas, glinides, dipeptidylpeptidase-4 inhibitors,glucagon-like peptide 1 receptor agonists), in addition to particularmechanisms dealing with delayed absorption of glucose bygastrointestinal tract. However, most of these medications have beenshown to have deleterious side effects such as weight gain, peripheraledema or congestive heart failure and to loss in efficiency in a longterm use.

Despite the increasing number of therapeutic options related todiabetes, none is able to reverse all the aspects of the diseaseincluding progressive loss of beta cells function and the management ofall the complications. Thus, there is a need for alternative andimproved medications for the treatment of diabetes and relatedconditions.

Pruritus, or itch, is a sensation that stimulates the desire or reflexto scratch, which can be either generalized or localized. The cause ofpruritus is not fully understood. Proposed contributors to thepathogenesis of pruritus may include anemia or other manifestation oferythropoietin deficiency, histamine release from skin mast cells, skindryness, secondary hyperparathyroidism, hyperphosphatemia with increasedcalcium phosphate deposition in the skin and alterations in theendogenous opioidergic system with overexpression of opioidmu-receptors. Chronic pruritus can seriously diminish the quality oflife in its sufferers as it can be intractable and incapacitating. It isa seriously debilitating condition, comparable to chronic pain, whichcan lead to frustration, desperation and depression. Moreover, chronicscratching often produces open skin lesions, subject to primary orsecondary infection, scarring and potential disfigurement. Chronicpruritus is often an indication of underlying disease and is alwayspresent in diseases such as urticaria and atopic dermatitis. Diagnosisof the underlying disease is desirable and clinical presentation,patient history, and patient self-evaluation form important parts ofsuch diagnosis. Pruritus is a well-known, frequent and distressingsymptom of cholestasis. In clinical practice, the most commonlyencountered cholestatic liver diseases (CLD) associated with pruritusare primary biliary cirrhosis (PBC), primary sclerosing cholangitis(PSC) and intrahepatic cholestasis of pregnancy. Cholestatic liverdiseases, or cholestasis, are a group of disorders of varying causesthat result when bile flow is impaired. Cholestasis can causeprogressive liver damage and eventually lead to end-stage liver disease.The mechanisms by which the liver is injured and fibrosis is stimulatedin cholestatic liver disease are unclear.

In exemplary embodiments, the invention provides a Colesevelam ColonSpecific Drug Delivery System for use in treatment of, for example,cholestasis and/or cholestatic pruritus.

In exemplary embodiments, the invention provides a Colesevelam ColonSpecific Drug Delivery System for use in treatment of, for example,inflammatory bowel diseases (IBD), irritable bowel syndrome, coloniccancer, cholestasis, cholestatic pruritus, insufficient control of bloodglucose, and cardiovascular disease, such as hypercholesterolemia.

All references cited herein are incorporated herein by reference intheir entireties.

BRIEF SUMMARY

The disclosure provides an oral drug delivery system comprising: a) acore comprising a therapeutically effective amount of at least oneactive agent present in an amount of from about about 35% to about 65%w/w of the core, and a drug release controlling component capable ofproviding release of the active agent primarily in a region selectedfrom the group consisting of the lower gastrointestinal tract, the largeintestine, the jejunum, the ileum, the cecum, the colon, the rectum, andcombinations thereof, b) an outer coating encasing the core, andoptionally a plasticizer, wherein after ingestion by a patient theactive agent is released primarily in the region selected from the groupconsisting of the lower gastrointestinal tract, the large intestine, thejejunum, the ileum, the cecum, the colon, the rectum, and combinationsthereof. The disclosure provides an oral drug delivery system whereinthe at least one active agent is selected from the group consisting ofcolesevelam, pharmaceutically acceptable salts thereof, derivativesthereof, and combinations thereof. The disclosure provides an oral drugdelivery system wherein the at least one active agent is present in anamount selected from the group consisting of about 250 mg, about 500 mg,about 625 mg, and about 650 mg. The disclosure provides an oral drugdelivery system wherein the at least one active agent is present in anamount of about 250 to about 650 mg. The disclosure provides an oraldrug delivery system wherein the therapeutically effective amount of theat least one active agent is present in an amount of from about 50% toabout 64% w/w of the core. The disclosure provides an oral drug deliverysystem wherein the therapeutically effective amount of the at least oneactive agent is present in an amount of about 63.13% w/w of the core.The disclosure provides an oral drug delivery system wherein the oraldrug delivery system releases the active agent primarily in the lowergastrointestinal tract. The disclosure provides an oral drug deliverysystem wherein about 80% to about 100% w/w of the at least one activeagent is released in the lower gastrointestinal tract. The disclosureprovides an oral drug delivery system wherein about 100% w/w of the atleast one active agent is released in the lower gastrointestinal tract.The disclosure provides an oral drug delivery system wherein the oraldrug delivery system releases the active agent primarily in the largeintestine. The disclosure provides an oral drug delivery system whereinabout 80% to about 100% w/w of the at least one active agent is releasedin the large intestine. The disclosure provides an oral drug deliverysystem wherein about 100% w/w of the at least one active agent isreleased in the large intestine. The disclosure provides an oral drugdelivery system wherein the oral drug delivery system releases theactive agent primarily in the colon. The disclosure provides an oraldrug delivery system wherein about 80% to about 100% w/w of the at leastone active agent is released in the colon. The disclosure provides anoral drug delivery system wherein about 100% w/w of the at least oneactive agent is released in the colon. The disclosure provides an oraldrug delivery system wherein the drug release controlling componentcapable of providing release of the active agent primarily in a regionselected from the group consisting of the lower gastrointestinal tract,the large intestine, the jejunum, the ileum, the cecum, the colon, therectum, and combinations thereof is at least one erodible matrixmaterial. The disclosure provides an oral drug delivery system whereinthe at least one erodible matrix material is selected from the groupconsisting of microcrystalline cellulose, hydroxypropyl methyl cellulose(HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), ethylhydroxy ethylcellulose (EHEC), andcombinations thereof. The disclosure provides an oral drug deliverysystem wherein the at least one erodible matrix material is present in aconcentration of about 20% to about 40% w/w of the core. The disclosureprovides an oral drug delivery system wherein the at least one erodiblematrix material is present in a concentration of about 5% to about 15%w/w of the core. The disclosure provides an oral drug delivery systemwherein the at least one erodible matrix material is present in aconcentration of about 8% to about 13% w/w of the core. The disclosureprovides an oral drug delivery system wherein the at least one erodiblematrix material is present in a concentration of about 12.12% w/w of thecore. The disclosure provides an oral drug delivery system wherein theerodible matrix material is microcrystalline cellulose. The disclosureprovides an oral drug delivery system wherein the erodible matrixmaterial is a combination if microcrystalline cellulose andhydroxypropyl methyl cellulose (HPMC). The disclosure provides an oraldrug delivery system wherein the core further comprises at least one ofthe following excipients: diluent, binding agent, lubricant,disintegrant, stabilizer, and combinations thereof. The disclosureprovides an oral drug delivery system wherein the core comprises adisintegrant, wherein the disintegrant comprises colloidal silicondioxide, in an amount of from about 0.1% to about 4% w/w of the core.The disclosure provides an oral drug delivery system wherein the corecomprises a lubricant, wherein the lubricant comprises magnesiumstearate, in an amount of from about 0.1% to about 4% w/w of the core.The disclosure provides an oral drug delivery system wherein the coatingis an enteric coating. The disclosure provides an oral drug deliverysystem wherein the coating allows the at least one active agentformulation to pass through the stomach substantially intact andsubsequently disintegrate substantially in the large intestine of apatient. The disclosure provides an oral drug delivery system whereinthe plasticizer is present in a concentration of about 0.5% to about 2%w/w of the outer coating. The disclosure provides an oral drug deliverysystem wherein the plasticizer is present in a concentration of about0.75% to about 1% w/w of the outer coating. The disclosure provides anoral drug delivery system wherein the plasticizer is present in aconcentration of about 0.87% w/w of the outer coating. The disclosureprovides an oral drug delivery system wherein the plasticizer isselected from the group consisting of dibutyl sebacate, diethylphthalate, triethyl citrate, tributyl citrate, and triacetin, acetylatedmonoglycerides, diacylated monoglyceride, phthalate esters, castor oil,and combinations thereof. The disclosure provides an oral drug deliverysystem wherein the plasticizer is diacylated monoglyceride.

The disclosure provides a method of preventing and/or treating pruritusin a patient in need thereof comprising: selecting a patient in need ofpreventing and/or treating pruritus; administering to the patient theoral drug delivery system of the disclosure, wherein pruritus isprevented and/or treated in the patient. The disclosure provides amethod of preventing and/or treating pruritus wherein the oral drugdelivery system is administered in single or divided doses of one tofour times daily. The disclosure provides a method of preventing and/ortreating pruritus wherein the pruritus is associated with cholestasis,cholestatic pruritus, or biliary pruritus. The disclosure provides amethod of preventing and/or treating pruritus wherein the pruritus isassociated with cholestatic liver disease. The disclosure provides amethod of preventing and/or treating pruritus further comprisingadministering one or more additional antipruritic agents. The disclosureprovides a method of preventing and/or treating pruritus wherein the oneor more additional antipruritic agents are selected from the groupconsisting of antihistamines, corticosteroids, immunomodulators,immunosuppressants, antidepressants and anticonvulsants.

The disclosure provides a method of preventing and/or treating adisorder related to elevated serum cholesterol concentration in apatient in need thereof comprising: selecting a patient in need ofpreventing and/or treating a disorder related to elevated serumcholesterol concentration; administering to the patient the oral drugdelivery system of the disclosure, wherein a disorder related toelevated serum cholesterol concentration is prevented and/or treated inthe patient. The disclosure provides a method of preventing and/ortreating a disorder related to elevated serum cholesterol concentrationin a patient in need thereof, wherein the oral drug delivery system isadministered in single or divided doses of one to four times daily. Thedisclosure provides a method of preventing and/or treating a disorderrelated to elevated serum cholesterol concentration in a patient in needthereof, further comprising administering one or more additional activeagents. The disclosure provides a method of preventing and/or treating adisorder related to elevated serum cholesterol concentration in apatient in need thereof, further comprising administering one or moreadditional active agents selected from the group consisting ofmevastatin, pravastatin, atorvastatin, rosuvastatin, cerivastatin,fluvastatin, lovastatin, and simvastatin, a fibric acid derivative,niacin, ezetimibe, probucol, raloxifene and its derivatives, and anunsaturated omega-3 fatty acid.

The disclosure provides a method of preventing and/or treatinginsufficient glycemic control in a patient in need thereof comprising:selecting a patient in need of preventing and/or treating insufficientglycemic control; administering to the patient the oral drug deliverysystem of the disclosure, wherein insufficient glycemic control isprevented and/or treated in the patient. The disclosure provides amethod of preventing and/or treating insufficient glycemic control in apatient in need thereof, wherein the oral drug delivery system isadministered in single or divided doses of one to four times daily. Thedisclosure provides a method of preventing and/or treating insufficientglycemic control in a patient in need thereof, further comprisingadministering one or more additional active agents. The disclosureprovides a method of preventing and/or treating insufficient glycemiccontrol in a patient in need thereof, further comprising administeringone or more additional active agents selected from the group consistingof metformin, sulphonylureas, thiazolidinediones, glinides,alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, and insulin andinsulin analogues; for example, despite mono-therapy with metformin, asulphonylurea, pioglitazone or (basal) insulin, or despite dualcombination therapy with a metformin/pioglitazone,metformin/sulphonylurea, metformin/(basal) insulin,sulphonylurea/pioglitazone, sulphonylurea/(basal) insulin orpioglitazone/(basal) insulin combination.

The disclosure provides a method for reducing elevated low-densitylipoprotein cholesterol (LDL) concentration a patient in need thereofcomprising: selecting a patient in need of reducing elevated LDLconcentration; administering to the patient the oral drug deliverysystem of the disclosure, wherein the LDL concentration is reduced inthe patient. The disclosure provides a method for reducing elevatedlow-density lipoprotein cholesterol (LDL) concentration a patient,wherein the oral drug delivery system is administered in single ordivided doses of one to four times daily. The disclosure provides amethod for reducing elevated low-density lipoprotein cholesterol (LDL)concentration a patient, further comprising administering one or moreadditional active agents. The disclosure provides a method for reducingelevated low-density lipoprotein cholesterol (LDL) concentration apatient, further comprising administering one or more additional activeagents selected from the group consisting of mevastatin, pravastatin,atorvastatin, rosuvastatin, cerivastatin, fluvastatin, lovastatin, andsimvastatin, a fibric acid derivative, niacin, ezetimibe, probucol,raloxifene and its derivatives, and an unsaturated omega-3 fatty acid.

The disclosure provides a method of preventing and/or treating bile acidmalabsorption diarrhea in a patient in need thereof comprising:selecting a patient in need of preventing and/or treating bile acidmalabsorption diarrhea; administering to the patient the oral drugdelivery system as disclosed herein, wherein bile acid malabsorptiondiarrhea is prevented and/or treated in the patient. The disclosureprovides a wherein the oral drug delivery system is administered insingle or divided doses of one to four times daily.

The disclosure provides for the use of the compositions of thedisclosure for the production of a medicament for treating theindications as set forth herein. In accordance with a furtherembodiment, the present disclosure provides a use of the pharmaceuticalcompositions described above, an amount effective for use in amedicament, and most preferably for use as a medicament for treating adisease or disorder in a subject. In accordance with yet anotherembodiment, the present disclosure provides a use of the pharmaceuticalcompositions described above, and at least one additional therapeuticagent, in an amount effective for use in a medicament, and mostpreferably for use as a medicament for treating a disease or disorderassociated with disease in a subject.

DETAILED DESCRIPTION

The disclosure relates to methods and materials for administering a bileacid sequestrant (e.g., colesevelam) to treat conditions associated withdiarrhea (e.g., bile acid malabsorption induced diarrhea). For example,the disclosure provides compositions and methods for treating diarrhea,such as bile acid malabsorption diarrhea, in a mammal, including withoutlimitation, a human, dog, cat, horse, pig, monkey, or sheep. Examples ofdiarrhea conditions that can be treated as described herein include,without limitation, bile acid malabsorption induced diarrhea, ilealresection diarrhea, radiation ileitis, Crohn's ileitis, acute Yersiniaileitis, diabetic diarrhea, diarrhea associated with small bowelbacterial overgrowth, irritable bowel syndrome with diarrhea,diarrhea-predominant irritable bowel syndrome, functional diarrhea, andpancreatic transplant associated diarrhea. Examples of bile acidsequestrants that can be used as described herein include, withoutlimitation, colesevelam, cholestyramine, colestipol, and chitosan. Insome cases, the methods provided herein can include identifying a mammal(e.g., human) to be treated.

As used herein the terms “Lower Gastrointestinal Tract” or “Lower GITract” refers to the lower part of the gastrointestinal tract thatincludes the jejunum and ileum of the small intestine and the largeintestine. (www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022856/). As usedherein the term “Large Intestine” refers to the part of the intestinethat includes the appendix, cecum, colon, and rectum. The largeintestine absorbs water from stool and changes it from a liquid to asolid form. (www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022246/).

As used herein the term “active pharmaceutical ingredient” (“API”) or“pharmaceutically active agent” is a drug or agent which can be employedfor the compositions and methods of the disclosure and is intended to beused in the human or animal body in order to heal, to alleviate, toprevent or to diagnose diseases, ailments, physical damage orpathological symptoms; allow the state, the condition or the functionsof the body or mental states to be identified; to replace activesubstances produced by the human or animal body, or body fluids; todefend against, to eliminate or to render innocuous pathogens, parasitesor exogenous substances or to influence the state, the condition or thefunctions of the body or mental states. Drugs in use can be found inreference works such as, for example, the Rote Liste or the Merck Index.Examples which may be mentioned include, for example, colesevelam.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the therapeutic compound is modifiedby making acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of the active agent. The pharmaceutically acceptable saltsinclude the conventional non-toxic salts, for example, from non-toxicinorganic or organic acids. For example, such conventional non-toxicsalts include those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and thelike; and the salts prepared from organic acids such as amino acids,acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and other known to those of ordinary skill in the pharmaceuticalsciences. Lists of suitable salts are found in texts such as Remington'sPharmaceutical Sciences, 18th Ed. (Alfonso R. Gennaro, ed.; MackPublishing Company, Easton, Pa., 1990); Remington: the Science andPractice of Pharmacy 19^(th) Ed. (Lippincott, Williams & Wilkins, 1995);Handbook of Pharmaceutical Excipients, 3^(rd) Ed. (Arthur H. Kibbe, ed.;Amer. Pharmaceutical Assoc., 1999); the Pharmaceutical Codex: Principlesand Practice of Pharmaceutics 12^(th) Ed. (Walter Lund ed.;Pharmaceutical Press, London, 1994); The United States Pharmacopeia: TheNational Formulary (United States Pharmacopeial Convention); and Goodmanand Gilman's: the Pharmacological Basis of Therapeutics (Louis S.Goodman and Lee E. Limbird, eds.; McGraw Hill, 1992), the disclosures ofwhich are hereby incorporated by reference.

An amount is “effective” as used herein, when the amount provides aneffect in the subject. As used herein, the term “effective amount” meansan amount of a compound or composition sufficient to significantlyinduce a positive benefit, including independently or in combinationsthe benefits disclosed herein, but low enough to avoid serious sideeffects, i.e., to provide a reasonable benefit to risk ratio, within thescope of sound judgment of the skilled artisan. For those skilled in theart, the effective amount, as well as dosage and frequency ofadministration, may be determined according to their knowledge andstandard methodology of merely routine experimentation based on thepresent disclosure.

As used herein, the terms “subject” and “patient” are usedinterchangeably. As used herein, the term “patient” refers to an animal,preferably a mammal such as a non-primate (e.g., cows, pigs, horses,cats, dogs, rats etc.) and a primate (e.g., monkey and human), and mostpreferably a human. In some embodiments, the subject is a non-humananimal such as a farm animal (e.g., a horse, pig, or cow) or a pet(e.g., a dog or cat). In a specific embodiment, the subject is anelderly human. In another embodiment, the subject is a human adult. Inanother embodiment, the subject is a human child. In yet anotherembodiment, the subject is a human infant.

As used herein, the phrase “pharmaceutically acceptable” means approvedby a regulatory agency of the federal or a state government, or listedin the U.S. Pharmacopeia, European Pharmacopeia, or other generallyrecognized pharmacopeia for use in animals, and more particularly, inhumans.

As used herein, the terms “prevent,” “preventing” and “prevention” inthe context of the administration of a therapy to a subject refer to theprevention or inhibition of the recurrence, onset, and/or development ofa disease or condition, or a combination of therapies (e.g., acombination of prophylactic or therapeutic agents).

As used herein, the terms “therapies” and “therapy” can refer to anymethod(s), composition(s), and/or agent(s) that can be used in theprevention, treatment and/or management of a disease or condition, orone or more symptoms thereof.

As used herein, the terms “treat,” “treatment,” and “treating” in thecontext of the administration of a therapy to a subject refer to thereduction or inhibition of the progression and/or duration of a diseaseor condition, the reduction or amelioration of the severity of a diseaseor condition, and/or the amelioration of one or more symptoms thereofresulting from the administration of one or more therapies.

As used herein, the term “about” when used in conjunction with a statednumerical value or range has the meaning reasonably ascribed to it by aperson skilled in the art, i.e. denoting somewhat more or somewhat lessthan the stated value or range.

Active Agent

As set forth above, the disclosure relates to methods and materials foradministering an active agent, such as a bile acid sequestrant (e.g.,colesevelam) to treat conditions associated with diarrhea (e.g., bileacid malabsorption induced diarrhea). Colesevelam hydrochloride(WELCHOL) is a bile acid sequestrant indicated as an adjunct to diet andexercise to reduce elevated low-density lipoprotein cholesterol (LDL-C)in adults with primary hyperlipidemia as monotherapy or in combinationwith an hydroxymethyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor;reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years ofage, with heterozygous familial hypercholesterolemia as monotherapy orin combination with a statin after failing an adequate trial of diettherapy; and improve glycemic control in adults with type 2 diabetesmellitus. Colesevelam hydrochloride is poly(allylamine hydrochloride)cross-linked with epichlorohydrin and alkylated with 1-bromodecane and(6-bromohexyl)-trimethylammonium bromide. The chemical name (IUPAC) ofcolesevelam hydrochloride is allylamine polymer with1-chloro-2,3-epoxypropane, [6-(allylamino)-hexyl]trimethylammoniumchloride and N-allyldecylamine, hydrochloride. The chemical structure ofcolesevelam hydrochloride is represented by the following formula:

In exemplary embodiments, formulations of the disclosure may compriseactive agent at a concentration of about 1%, about 2%, about 3%, about4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%,about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%,about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%,about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%, Inexemplary embodiments, formulations of the disclosure may compriseactive agent at a concentration of about 1 to 20%, of about 5% to 25%,about 10% to about 20%, or about 15% to about 18%, about 30% to about70%, about 35% to about 65%, about 63.13%, and about 40% to about 64%w/w.

In exemplary tablets of the disclosure, the active agent will representapproximately 1 wt % to 75 wt %, preferably 2 wt % to 30 wt %, morepreferably 5 wt. % to 20 wt. % of the core.

Gastrointestinal Tract

The small intestine extends from the pylorus to the colic valve where itends in the large intestine. The small intestine is about 6 meters longand is divisible into three portions: the duodenum, the jejunum, and theileum. The small intestine is especially adapted for transport andabsorption of nutrients and other molecules from ingested material,passing through the lining of the small intestine into the blood. Thesurface cells of the small intestine are highly specialized fordigestion and absorption of nutrients. Almost all the body's nutrientabsorption occurs in the small intestine, along its three sub-divisions:the duodenum, jejunum, and ileum. Sites for absorption of specificnutrients (egg: iron, vitamin B12) are located in these divisions, butmost absorption occurs in the jejunum (middle section). Specializedcells contain digestive enzymes, carrier proteins and other secretions.Blood vessels transport nutrients away from the intestine to the liverin the first instance.

Indigestible food passes into the large intestine. By the time ingestedmaterial leaves the small intestine, virtually all nutrient absorptionwill have occurred. The large intestine extends from the end of theileum (distal ileum) to the anus. The large intestine is divided intothe cecum, colon, rectum, and anal canal. The colon is divided into fourparts: the ascending, transverse, descending, and sigmoid. Thesubstantial release of the active agent of the present disclosure mayoccur in any portion of the large intestine. In one embodiment, releaseprimarily occurs at the upper regions of the large intestine, such as,for example, at the distal ileum, cecum, and/or the ascending colon.

It is known that there are major variations in acidity in thegastrointestinal tract. The stomach is a region of high acidity (aboutpH 1 to 3). Specific glands and organs emptying into the small intestineraise the pH of the material leaving the stomach to approximately pH 6.0to 6.5. The large intestine and the colon are about pH 6.4 to 7.0. Thetransit time through the small intestine is approximately three hours.In contrast, the transit time through the large intestine isapproximately 35 hours.

Pruritic Conditions

According to the present disclosure, pruritus includes any itchy orpruritic condition, e.g., a sensation that causes the desire or reflexto scratch. In some embodiments, compositions and methods of thedisclosure are used for the treatment of a subject suffering from apruritic condition selected from the group consisting of atopicdermatitis, nervous dermatitis, contact dermatitis, seborrheicdermatitis, autosensitization dermatitis, caterpillar dermatitis,asteatosis, senile pruritus cutaneous, insect sting, photosensitivedermatosis, urticarial, prurigo, herpes, impetigo, eczema, tinea,lichen, psoriasis, scabies and acne vulgaris, visceral diseasescomplicated with pruritus such as malignant tumors, diabetes mellitus,hepatic diseases, renal failure, hemodialysis, peritoneal dialysis, andpregnancy. Chronic pruritus on non-inflamed skin may result fromdermatological diseases, including atopic diathesis, asteatosis,porphyria, suburticarial stages of solar injury, cholinergic, adrenergicurticaria, initial stage of mastocytosis, bullous pemphigoid, andDuhring's disease (dermatitis herpetiformis); from endocrine andmetabolic disorders, such as chronic renal insufficiency and thedialysis needed treat it, hepatopathies with cholestasis, diabetesmellitus, malabsorption disorders, anorexia, gluten-enteropathies,hyperthyroidism, hypothyroidism, hyperparathyroidism, and perimenopausalpruritus; from infections including HIV infection, parasites,Helicobacter pylori, and helminth-related; from hemotological andlymphoproliferative diseases such as iron deficiency, polycythaemicavera, hypereosinophilia syndrome, myelodysplastic syndrome, Hodgkin'sdisease, non-Hodgkin's lymphoma, plasmocytoma, and systemicmastocytosis; from solid malignant tumors including cervical, breast,prostate or large intestinal cancer, and carcinoid tumors; fromneurological disorders such as brachioradial pruritus, notalgiaparesthetica, post-zoster neuralgia, vulvodynia, neuropathies of variousorigin, multiple sclerosis, tumors, abscesses, underperfusion,infarctions involving the CNS/spinal cord; from psychogenic disorderssuch as depression, schizophrenia, and tactile hallucinations; and fromintrahepatic cholestasis in pregnant women (pruritus gravidarum).

Chronic pruritus on inflamed skin may be observed in patients withinflammatory skin disease including, but not limited to, atopicdermatitis, allergic, irritant contact dermatitis, exsiccationdermatitis, nummular and dyshidrotic dermatitis, lichen planus, lichensclerosus et atrophicus, polymorphous light eruption psoriasis, Grover'sdisease, mucinosis, mastocytosis, and urticaria; infectious skindiseases such as mycoses, bacterial and viral infections, scabies,pediculosis, insect bites, and folliculitides; autoimmune skin diseasesincluding Bullous skin disorders, especially dermatitis herpetiformis(Duhring's disease), and bullous pemphigoid; genodermatoses such asDarier's disease, and Hailey-Hailey disease; pregnancy-related skindiseases including polymorphic eruption of pregnancy (PEP, formerlyknown as PUPPP), atopic eruption of pregnancy, and pemphigoidgestationis; and neoplasias such as cutaneous T-cell lymphoma(especially the erythrodermic form).

Prurigo nodularis (PN), or nodular prurigo, is a particularly severeform of chronic itching that may treated by methods and compositions ofthe present disclosure. Characterized by itchy, excoriated, lichenifiedpapules and nodules, PN can occur at any age, but most often presents inmiddle-aged and elderly patients on their arms and legs (E. Weisshaarand S. Stander, Acta Derm. Venereol., 2012, 92:532-533). The etiology ofPN is unknown, but it usually occurs in patients with a personal orfamily history of atopic dermatitis, and often with concomitant medicalconditions such as hepatic or renal function, local trauma or insult tothe skin, infection, and HIV or other immunodeficiencies. PN may resultin permanent changes to the skin, including nodular lichenification,hyperkeratosis, hyperpigmentation, and skin thickening.

In some embodiments, methods of the present disclosure are used for thetreatment of a subject suffering from a pruritic condition associatedwith a skin change. For example, such pruritic condition can be selectedfrom the group consisting of pruritus secondary to inflamed skin (e.g.,atopic dermatitis, psoriasis, burns); pruritus arising from conditionsof non-diseased skin (e.g., uremic pruritus, cholestatic pruritus,cancers, hydroxyetheyl starch induced pruritus), and pruritus associatedwith chronic secondary scratch or other types of skin lesions that mayor may not be the result of an underlying medical condition (e.g.,prurigo nodularis) and the underlying disease is categorized based onhistological, radiological or other investigations as being of an originselected from the group consisting of dermatologic origin, systemicdisease origin, neurologic origin, psychogenic origin, mixed origin, orother origin.

In some embodiments, compositions and methods of the present disclosureare used for the treatment of a subject suffering from a pruriticcondition associated with neurogenic inflammation of the skin, e.g.,prurigo nodularis, atopic dermatitis, burn pruritus, burn, woundhealing, etc. In some other embodiments, methods of the presentdisclosure are used for the treatment of a subject suffering from apruritic condition associated with neurogenic inflammation with elevatedsubstance P level. In still some other embodiments, methods of thepresent disclosure are used for the treatment of a subject sufferingfrom a pruritic condition associated with elevated substance P level.

In some embodiments, compositions and methods of the present disclosureare used for the treatment of a subject suffering from a pruriticcondition associated with one or more related or unrelated conditions.For example, the pruritic condition can be associated with adermatologic condition including aquagenic pruritus, atopic dermatitis,idiopathic pruritus, Lichen simplex chronicus, prurigo nodularis,psoriasis, and scabies. In another example, the pruritic condition canbe associated with a hematological or oncological condition includingcancer related pruritus, chemotherapy induced pruritus, HIV proteaseinhibitor induced pruritus, Hodgkin's lymphoma associated pruritus,polycythemia vera, etc. In another example, the pruritic condition canbe associated with a metabolic condition including cholestatic pruritus,uremic pruritus, etc. In still another example, the pruritic conditioncan be associated with a condition of pain or neurological conditionincluding brachioradial pruritus, burn induced pruritus, neuropathicpruritus, morphine induced pruritus, multiple sclerosis associatedpruritus, post herpetic pruritus, pruritus associated with psychiatriccauses, etc.

In one embodiment, compositions and methods of the present disclosureare used for the treatment of uremic pruritus. In another embodiment,methods of the present disclosure are used for the treatment of prurigonodularis. In yet another embodiment, compositions and methods of thepresent disclosure are used to treat human beings. In still anotherembodiment, methods of the present disclosure are used to treat animalsother than human beings.

Cardiovascular Disease

Aspects of the present specification disclose, in part, a method oftreating an individual with a cardiovascular disease. In one embodiment,the method comprises the step of administering to an individual in needthereof a pharmaceutical composition disclosed herein, whereinadministration reduces a symptom associated with the cardiovasculardisease, thereby treating the individual.

Aspects of the present specification disclose, in part, treating anindividual suffering from a cardiovascular disease. As used herein, theterm “treating,” refers to reducing or eliminating in an individual aclinical symptom of a cardiovascular disease; or delaying or preventingin an individual the onset of a clinical symptom of a cardiovasculardisease. For example, the term “treating” can mean reducing a symptom ofa condition characterized by a cardiovascular disease by, e.g., at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90% at least95%, or at least 100%. The actual symptoms associated with acardiovascular disease are well known and can be determined by a personof ordinary skill in the art by taking into account factors, including,without limitation, the location of the cardiovascular disease, thecause of the cardiovascular disease, the severity of the cardiovasculardisease, and/or the tissue or organ affected by the cardiovasculardisease. Those of skill in the art will know the appropriate symptoms orindicators associated with a specific type of cardiovascular disease andwill know how to determine if an individual is a candidate for treatmentas disclosed herein.

Cardiovascular disease is any of a number of specific diseases thataffect the heart itself and/or the blood vessel system, especially theveins and arteries leading to and from the heart. Known and/orassociated causes of a cardiovascular disease include, withoutlimitation, unhealthy ratios of the two smallest lipoproteins LDL andHDL, hyperlipidemia, elevated blood glucose levels, upper normal andhigh blood pressure, Lp-PLA2, lipoprotein(a) and hyperhomocysteinemia.Symptoms of a cardiovascular disorder affecting the heart include,without limitation, chest pain, chest discomfort, and pain in one orboth arms, one or both shoulders, neck, jaw, or back, shortness ofbreath, dizziness, faster heartbeats, nausea, abnormal heartbeats,fatigue, and/or myocardial infarction. Symptoms of a cardiovasculardisorder affecting the brain include, without limitation, suddennumbness or weakness of the face, one or both arms, or one or both legs,sudden confusion or trouble speaking or understanding speech, suddentrouble seeing in one or both eyes, sudden dizziness, difficultywalking, or loss of balance or coordination, and/or sudden severeheadache with no known cause. Symptoms of a cardiovascular disorderaffecting one or both leg, pelvis, one or both arms, and/or shoulderinclude, without limitation, muscle pain, muscle cramp, cold sensationin one or both feet and/or toes, one or both hands and/or fingers,and/or numbness or weakness in one or both feet and/or toes, one or bothhands and/or fingers.

There are more than 60 types of cardiovascular disease including,without limitation, a hyperlipidemia, a coronary heart disease, anatherosclerosis, a peripheral vascular disease, a cardiomyopathy, avasculitis, an inflammatory heart disease, an ischemic heart disease, acongestive heart failure, a hypertensive heart disease, a valvular heartdisease, a hypertension, myocardial infarction, a diabetic cardiacconditions, an aneurysm; an embolism, a dissection, a pseudoaneurysm, avascular malformation, a vascular nevus, a thrombosis, a varicose vein,and a stroke.

In one embodiment, a cardiovascular disease comprises a hyperlipidemia.A hyperlipidemia (or hyperlipoproteinemia) refers to a conditioncharacterized by abnormally elevated levels of lipids and/orlipoproteins in the blood. Hyperlipidemias may be classified as familial(or primary) when caused by specific genetic abnormalities, acquired (orsecondary) when resulting from another underlying disorder, oridiopathic, when of unknown cause. Hyperlipidemias may also beclassified based on which types of lipids and/or lipoproteins areelevated. Non-limiting examples of a hyperlipidemia includedyslipidemia, hypercholesterolemia, hyperglyceridemia,hypertriglyceridemia, hyperlipoproteinemia, and hyperchylomicronemia,and combined hyperlipidemia. Hyperlipoproteinemia include, e.g.,hyperlipoproteinemia type Ia, hyperlipoproteinemia type Ib,hyperlipoproteinemia type Ic, hyperlipoproteinemia type IIa,hyperlipoproteinemia type IIb, hyperlipoproteinemia type III,hyperlipoproteinemia type IV, and hyperlipoproteinemia type V.

In another embodiment, a cardiovascular disease comprises a coronaryheart disease. A coronary heart disease refers to a conditioncharacterized by failure of the coronary circulation to supply adequateblood flow to cardiac muscle and surrounding tissue. Typically caused bythe narrowing or blockage of the coronary artery, such as, e.g., anatherosclerotic coronary artery disease, a coronary vasospasm, and/or acoronary stenosis. Chest pain and myocardial infarction are commonsymptoms of and conditions caused by coronary heart disease.

In another embodiment, a cardiovascular disease comprises a vascularocclusive disease (VOD). A VOD refers to a condition characterized by anobstruction of a blood vessel. A VOD includes, without limitation, anatherosclerosis, a peripheral vascular disease, and a stenosis. In anaspect of this embodiment, a VOD comprises an atherosclerosis. Anatherosclerosis refers to a condition characterized by a buildup ofcholesterol and fatty deposits (called plaques) on the inner walls ofthe arteries. These plaques can restrict blood flow to the heart muscleby physically clogging the artery or by causing abnormal artery tone andfunction. Rupture of atherosclerotic plaque is the most common cause ofan ischemia.

In an aspect of this embodiment, a VOD comprises a peripheral vasculardisease (PVD). Peripheral vascular disease (PVD), also known asperipheral arterial disease (PAD) or peripheral artery occlusive disease(PAOD), refers to a condition characterized by an obstruction of largearteries not within the coronary, aortic arch vasculature, or brain. PVDcan result from atherosclerosis, an inflammatory processes leading tostenosis, an embolism, or thrombus formation. It causes either acute orchronic ischemia. PVD also includes a subset of diseases classified asmicrovascular diseases resulting from episodic narrowing of thearteries, such as, e.g., Raynaud's phenomenon, or widening of thearteries, such as, e.g., a vascular spasm. Symptoms of PVD include,without limitation, pain, weakness, numbness, or cramping in muscles dueto decreased blood flow, sores, wounds, or ulcers that heal slowly ornot at all, blueness or paleness in limb, coolness in limb, diminishedhair and nail growth on affected limb and digits. About 20% of patientswith mild PAD may be asymptomatic.

In another embodiment, a cardiovascular disease comprises acardiomyopathy. A cardiomyopathy refers to a condition characterized bythe deterioration of myocardium function. Symptoms and signs may mimicthose of almost any form of heart disease and include chest pain and EKGabnormalities. A mild cardiomyopathy is frequently asymptomatic. A moresevere case is associated with heart failure, arrhythmias, systemicembolization and/or sudden cardiac death. A cardiomyopathy may beclassified functionally, as involving dilation, hypertrophy, orrestriction.

In another embodiment, a cardiovascular disease comprises a vasculitis.Vasculitis is a varied group of disorders featuring inflammation of avessel wall including lymphatic vessels and blood vessels like veins(phlebitis), arteries (arteritis) and capillaries due to leukocytemigration and resultant damage. In another embodiment, a cardiovasculardisease comprises an inflammatory heart disease. An inflammatory heartdisease refers to a condition characterized by inflammation of the heartmuscle and/or the tissue surrounding it. Non-limiting examples ofinflammatory heart disease include endocarditis, inflammatorycardiomegaly, and myocarditis.

In another embodiment, a cardiovascular disease comprises an ischemicheart disease. Ischemic heart disease, or myocardial ischemia, refers toa condition characterized by reduced blood supply of the heart muscle,usually due to a narrowing or blockage of a coronary artery. Symptoms ofischemic heart disease include chest pain on exertion, in cold weatheror emotional situations, acute chest pain, acute coronary syndrome,unstable angina, myocardial infarction, heart failure, difficulty inbreathing or swelling of the extremities.

In another embodiment, a cardiovascular disease comprises a congestiveheart failure. A congestive heart failure, or congestive cardiacfailure, refers to a condition characterized by a heart abnormality thatcannot result from any structural or functional cardiac disorder thatimpairs the ability of the heart to fill with or pump a sufficientamount of blood throughout the body.

In another embodiment, a cardiovascular disease comprises a hypertensiveheart disease. A hypertensive heart disease refers to a conditioncharacterized by high blood pressure, especially localized high bloodpressure. Conditions that can be caused by hypertensive heart diseaseinclude, without limitation, left ventricular hypertrophy, coronaryheart disease, congestive heart failure, hypertensive cardiomyopathy,and cardiac arrhythmias.

In another embodiment, a cardiovascular disease comprises a valvularheart disease. A valvular heart disease refers to a conditioncharacterized by a malfunction of one or more valves of the heart. Majorheart valves which may be affected by valvular heart disease, including,without limitation, tricuspid valve, right aortic valve, mitral valve,and left aortic valve.

A composition or compound is administered to an individual. Anindividual is typically a human being. Typically, any individual who isa candidate for a conventional cardiovascular disease treatment is acandidate for a cardiovascular disease treatment disclosed herein.Pre-operative evaluation typically includes routine history and physicalexamination in addition to thorough informed consent disclosing allrelevant risks and benefits of the procedure.

The compounds and compositions as disclosed, for example, bile acidsequestrants such as cholestyramine, colestipol, and colesevelam, mayalso be advantageously combined and/or used in combination with otherlipid-regulating agents, different from the subject compounds. In manyinstances, administration in combination with the disclosed compoundsand compositions enhances the efficacy of such modulators.Lipid-regulating agents may include, but are not limited to, statins,otherwise known as HMG-CoA reductase inhibitors, such as mevastatin,pravastatin, atorvastatin, rosuvastatin, cerivastatin, fluvastatin,lovastatin, and simvastatin; niacin, or nicotinic acid, and itsderivatives; fibrates such as gemfibrozil, clofibrate, fenofibrate,benzafibrate and cipofibrate; probucol; raloxifene and its derivatives;absorption inhibitors such as ACAT inhibitors, β-lactam, sulfatedpolysaccharides, steroidal glycosides, and azetidinone compounds,including but not limited to ezetimibe, and others described above;unsaturated omega-3 fatty acids; and mixtures thereof.

Diabetes and Related Disorders

The drugs or combinations as disclosed herein may be used to normalizeblood glucose level by acting e.g., on insulin release, glucagonrelease, glucose utilization and/or glucose production, and offer novelpotent therapies of diabetes and related disorders. The drugs andcombinations have a strong effect on diabetes' relevant functions: theyare involved in the protection of beta cells against apoptosis, theincrease of glucose uptake in muscular tissues and in adipocytes, theincrease of insulin secretion by the pancreatic β cells and/or in thecontrol of glucose production in hepatic tissues.

These drugs and combinations therefore represent new therapeuticapproaches for the control of blood glucose level in a mammalian in needthereof. They also represent new therapeutic approaches for thetreatment of diabetes or related disorders in a mammalian in needthereof.

In this regard, aspects of the present specification relate tocompositions comprising at least one compound selected from the groupconsisting of colesevelam, pharmaceutically acceptable salts thereof,derivatives thereof, and combinations thereof to a patient in needthereof. Aspects of the present specification relate to compositionscomprising bile acid sequestrants such as cholestyramine, colestipol,and colesevelam.

Aspects of the present specification also relates to the use of at leastone compound selected from the group consisting of colesevelam,pharmaceutically acceptable salts thereof, derivatives thereof, andcombinations thereof for the manufacture of a medicament for treatingdiabetes or a related disorder in a patient in need thereof. Aspects ofthe present specification also relates to the use of bile acidsequestrants such as cholestyramine, colestipol, and colesevelam for themanufacture of a medicament for treating diabetes or a related disorderin a patient in need thereof

Within the scope of the present disclosure it has now surprisingly beenfound that at least one compound selected from the group consisting ofcolesevelam, pharmaceutically acceptable salts thereof, derivativesthereof, and combinations thereof as defined herein have unexpected andparticularly advantageous properties, which make them particularlysuitable for treating and/or preventing (including preventing or slowingthe progression or delaying the onset) of metabolic diseases,particularly diabetes (especially type 2 diabetes mellitus) andconditions related thereto (e.g., diabetic complications), in advancedor late stage type 2 diabetes patients, including patients withinsufficient glycemic control despite a therapy with an oral and/or anon-oral antidiabetic drug and/or with indication on insulin.

Thus, the present disclosure provides at least one compound selectedfrom the group consisting of colesevelam, pharmaceutically acceptablesalts thereof, derivatives thereof, and combinations thereof as definedherein for use in the treatment of patients with insufficient glycemiccontrol despite a therapy (including mono-, dual or triple medication)with one or more conventional oral antidiabetic drugs selected frommetformin, sulphonylureas, thiazolidinediones, glinides andα-glucosidase inhibitors.

In another embodiment, the present disclosure provides at least onecompound selected from the group consisting of colesevelam,pharmaceutically acceptable salts thereof, derivatives thereof, andcombinations thereof as defined herein for use in the treatment ofpatients with insufficient glycemic control despite therapy (includingmono-, dual or triple medication) with one, two or three conventionaloral or non-oral antidiabetic drugs selected from metformin,sulphonylureas, thiazolidinediones, glinides, alpha-glucosidaseblockers, GLP-1 and GLP-1 analogues, and insulin and insulin analogues;for example, despite mono-therapy with metformin, a sulphonylurea,pioglitazone or (basal) insulin, or despite dual combination therapywith a metformin/pioglitazone, metformin/sulphonylurea,metformin/(basal) insulin, sulphonylurea/pioglitazone,sulphonylurea/(basal) insulin or pioglitazone/(basal) insulincombination.

The present disclosure further provides at least one compound selectedfrom the group consisting of colesevelam, pharmaceutically acceptablesalts thereof, derivatives thereof, and combinations thereof as definedherein for use in the treatment of diabetes patients with insufficientglycemic control despite mono-therapy with a sulphonylurea, or despitedual combination therapy with a metformin/sulphonylurea,sulphonylurea/pioglitazone or sulphonylurea/(basal) insulin combination.

In particular, the present disclosure provides at least one compoundselected from the group consisting of colesevelam, pharmaceuticallyacceptable salts thereof, derivatives thereof, and combinations thereofas defined herein for use in the treatment of patients with insufficientglycemic control despite a therapy with a sulphonylurea drug.

The present disclosure further provides at least one compound selectedfrom the group consisting of colesevelam, pharmaceutically acceptablesalts thereof, derivatives thereof, and combinations thereof as definedherein for use in the treatment and/or prevention of metabolic diseases,particularly type 2 diabetes mellitus, in patients with insufficientglycemic control despite a therapy with a sulphonylurea drug.

The present disclosure further provides at least one compound selectedfrom the group consisting of colesevelam, pharmaceutically acceptablesalts thereof, derivatives thereof, and combinations thereof as definedherein for use in the treatment and/or prevention of diabetes withsecondary sulphonylurea failure.

The present disclosure further provides the use of at least one compoundselected from the group consisting of colesevelam, pharmaceuticallyacceptable salts thereof, derivatives thereof, and combinations thereofas defined herein for the manufacture of a pharmaceutical compositionfor treating and/or preventing metabolic diseases, particularly type 2diabetes mellitus, in patients with insufficient glycemic controldespite a therapy with a sulphonylurea drug.

The present disclosure further provides a pharmaceutical composition foruse in the treatment and/or prevention of metabolic diseases,particularly type 2 diabetes mellitus, in patients with insufficientglycemic control despite a therapy with a sulphonylurea drug, saidpharmaceutical composition comprising at least one compound selectedfrom the group consisting of colesevelam, pharmaceutically acceptablesalts thereof, derivatives thereof, and combinations thereof as definedherein and optionally one or more pharmaceutically acceptable carriersand/or diluents.

Aspects of the specification relate to a fixed or non-fixed combinationincluding a kit-of-parts for use in the treatment and/or prevention ofmetabolic diseases, particularly type 2 diabetes mellitus, in patientswith insufficient glycemic control despite a therapy with asulphonylurea drug, said combination comprising a At least one compoundselected from the group consisting of colesevelam, pharmaceuticallyacceptable salts thereof, derivatives thereof, and combinations thereofas defined herein and optionally one or more other active substances,e.g., any of those mentioned herein.

The present disclosure further provides the use of at least one compoundselected from the group consisting of colesevelam, pharmaceuticallyacceptable salts thereof, derivatives thereof, and combinations thereofas defined herein in combination with one or more other activesubstances, such as e.g., any of those mentioned herein, for themanufacture of a pharmaceutical composition for treatment and/orprevention of metabolic diseases, particularly type 2 diabetes mellitus,in patients with insufficient glycemic control despite a therapy with asulphonylurea drug.

The present disclosure further provides a pharmaceutical composition foruse in the treatment and/or prevention of metabolic diseases,particularly type 2 diabetes mellitus, in patients with insufficientglycemic control despite a therapy with a sulphonylurea drug, saidpharmaceutical composition comprising at least one compound selectedfrom the group consisting of colesevelam, pharmaceutically acceptablesalts thereof, derivatives thereof, and combinations thereof as definedherein and optionally one or more other active substances, such as e.g.,any of those mentioned herein, such as e.g., for separate, sequential,simultaneous, concurrent or chronologically staggered use of the activeingredients.

The present disclosure further provides a method of treating and/orpreventing metabolic diseases, particularly type 2 diabetes mellitus, inpatients with insufficient glycemic control despite a therapy with asulphonylurea drug, said method comprising administering to a subject inneed thereof (particularly a human patient) an effective amount of atleast one compound selected from the group consisting of colesevelam,pharmaceutically acceptable salts thereof, derivatives thereof, andcombinations thereof as defined herein, optionally alone or incombination, such as e.g., separately, sequentially, simultaneously,concurrently or chronologically staggered, with an effective amount ofone or more other active substances, such as e.g., any of thosementioned herein.

In addition, aspects of the specification relate to at least onecompound selected from the group consisting of colesevelam,pharmaceutically acceptable salts thereof, derivatives thereof, andcombinations thereof as defined herein, optionally in (add-on orinitial) combination with one or two conventional antihyperglycemicagents selected from metformin, sulphonylureas, thiazolidinediones(e.g., pioglitazone), glinides, alpha-glucosidase blockers, GLP-1 orGLP-1 analogues, and insulin or insulin analogues, for use in patientswith insufficient glycemic control despite therapy with (e.g., ifapplicable, despite therapy with a maximal tolerated oral dose of) one,two or three conventional antihyperglycemic agents selected frommetformin, sulphonylureas, thiazolidinediones, glinides,alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and insulin orinsulin analogues (e.g., despite mono-therapy with metformin, asulphonylurea, pioglitazone or (basal) insulin, or despite dualcombination therapy with a metformin/pioglitazone,metformin/sulphonylurea, metformin/(basal) insulin,sulphonylurea/pioglitazone, sulphonylurea/(basal) insulin orpioglitazone/(basal) insulin combination).

In a further embodiment of the present disclosure, it is provided atleast one compound selected from the group consisting of colesevelam,pharmaceutically acceptable salts thereof, derivatives thereof, andcombinations thereof as defined herein, optionally in combination withone conventional antihyperglycemic agent selected from metformin,sulphonylureas, thiazolidinediones (e.g., pioglitazone), glinides,alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, and insulin andinsulin analogues, for use in (second line) therapy of type 2 diabetespatients who are insufficiently controlled on said conventionalantihyperglycemic agent alone.

In a further embodiment of the present disclosure, it is provided atleast one compound selected from the group consisting of colesevelam,pharmaceutically acceptable salts thereof, derivatives thereof, andcombinations thereof as defined herein, optionally in combination withtwo conventional antihyperglycemic agents selected from metformin,sulphonylureas, thiazolidinediones (e.g., pioglitazone), glinides,alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, and insulin andinsulin analogues, for use in (third line) therapy of type 2 diabetespatients who are insufficiently controlled on a dual combination of saidconventional antihyperglycemic agents.

In a further embodiment of the present disclosure, it is provided atleast one compound selected from the group consisting of colesevelam,pharmaceutically acceptable salts thereof, derivatives thereof, andcombinations thereof as defined herein, in combination with aconventional antihyperglycemic agent selected from the group consistingof metformin, pioglitazone, a sulphonylurea, and insulin; for use intherapy of type 2 diabetes patients with insufficient glycemic controlon the conventional antihyperglycemic agent alone.

In a further embodiment of the present disclosure, it is provided atleast one compound selected from the group consisting of colesevelam,pharmaceutically acceptable salts thereof, derivatives thereof, andcombinations thereof as defined herein, in combination with twoconventional antihyperglycemic agents selected from the group consistingof the following combinations: metformin and pioglitazone, metformin anda sulphonylurea, metformin and insulin, a sulphonylurea andpioglitazone, a sulphonylurea and insulin, and pioglitazone and insulin;for use in therapy of type 2 diabetes patients with insufficientglycemic control on the two conventional antihyperglycemic agents.

In particular, the present disclosure provides at least one compoundselected from the group consisting of colesevelam, pharmaceuticallyacceptable salts thereof, derivatives thereof, and combinations thereofas defined herein in combination with a sulphonylurea for use in thetreatment of type 2 diabetes patients with insufficient glycemic controldespite mono-therapy with a maximal tolerated dose of a sulphonylurea.

Further, the present disclosure provides at least one compound selectedfrom the group consisting of colesevelam, pharmaceutically acceptablesalts thereof, derivatives thereof, and combinations thereof as definedherein in combination with a sulphonylurea and metformin for use in thetreatment of type 2 diabetes patients with insufficient glycemic controldespite dual combination therapy with a sulphonylurea and metformin.

Further, the present disclosure provides at least one compound selectedfrom the group consisting of colesevelam, pharmaceutically acceptablesalts thereof, derivatives thereof, and combinations thereof as definedherein in combination with a sulphonylurea and pioglitazone for use inthe treatment of type 2 diabetes patients with insufficient glycemiccontrol despite dual combination therapy with a sulphonylurea andpioglitazone.

Further, the present disclosure provides at least one compound selectedfrom the group consisting of colesevelam, pharmaceutically acceptablesalts thereof, derivatives thereof, and combinations thereof as definedherein in combination with a sulphonylurea and insulin for use in thetreatment of type 2 diabetes patients with insufficient glycemic controldespite dual combination therapy with a sulphonylurea and insulin.

The present disclosure further provides the use of at least one compoundselected from the group consisting of colesevelam, pharmaceuticallyacceptable salts thereof, derivatives thereof, and combinations thereofas defined herein, optionally in combination with one or more otheractive substances, such as e.g., any of those mentioned herein, for oneor more of the following purposes:

-   -   for preventing, slowing progression of, delaying, or treating a        metabolic disorder;    -   for improving glycemic control and/or for reducing of fasting        plasma glucose, of postprandial plasma glucose and/or of        glycosylated hemoglobin HbA1c;    -   for preventing, slowing progression of, delaying or treating of        a condition or disorder selected from the group consisting of        complications of diabetes mellitus;    -   for reducing the weight or preventing an increase of the weight        or facilitating a reduction of the weight;    -   for preventing or treating the degeneration of pancreatic beta        cells and/or for improving and/or restoring the functionality of        pancreatic beta cells and/or stimulating and/or restoring the        functionality of pancreatic insulin secretion; and/or    -   for maintaining and/or improving the insulin sensitivity and/or        for treating or preventing hyperinsulinemia and/or insulin        resistance; in diabetes patients with insufficient glycemic        control despite a therapy with an oral antidiabetic drug,        particularly a sulphonylurea drug (secondary SU failure).

Examples of such metabolic diseases or disorders amenable by the therapyof this disclosure in patients with secondary oral antidiabetic drugfailure may include, without being restricted to, Type 1 diabetes, Type2 diabetes, inadequate glucose tolerance, insulin resistance,hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia,metabolic syndrome X, obesity, hypertension, chronic systemicinflammation, retinopathy, neuropathy, nephropathy, atherosclerosis,endothelial dysfunction and osteoporosis.

The present disclosure further provides the use of at least one compoundselected from the group consisting of colesevelam, pharmaceuticallyacceptable salts thereof, derivatives thereof, and combinations thereofas defined herein, optionally in combination with one or more otheractive substances, such as e.g., any of those mentioned herein, for themanufacture of a medicament for one or more of the following purposes:

-   -   preventing, slowing the progression of, delaying or treating a        metabolic disorder or disease, such as e.g., type 1 diabetes        mellitus, type 2 diabetes mellitus, impaired glucose tolerance        (IGT), impaired fasting blood glucose (IFG), hyperglycemia,        postprandial hyperglycemia, overweight, obesity, dyslipidemia,        hyperlipidemia, hypercholesterolemia, hypertension,        atherosclerosis, endothelial dysfunction, osteoporosis, chronic        systemic inflammation, non alcoholic fatty liver disease        (NAFLD), retinopathy, neuropathy, nephropathy and/or metabolic        syndrome;    -   improving glycemic control and/or for reducing of fasting plasma        glucose, of postprandial plasma glucose and/or of glycosylated        hemoglobin HbA1c;    -   preventing, slowing, delaying or reversing progression from        impaired glucose tolerance (IGT), impaired fasting blood glucose        (IFG), insulin resistance and/or from metabolic syndrome to type        2 diabetes mellitus;    -   preventing, reducing the risk of, slowing the progression of,        delaying or treating of complications of diabetes mellitus such        as micro- and macrovascular diseases, such as nephropathy,        micro- or macroalbuminuria, proteinuria, retinopathy, cataracts,        neuropathy, learning or memory impairment, neurodegenerative or        cognitive disorders, cardio- or cerebrovascular diseases, tissue        ischaemia, diabetic foot or ulcus, atherosclerosis,        hypertension, endothelial dysfunction, myocardial infarction,        acute coronary syndrome, unstable angina pectoris, stable angina        pectoris, peripheral arterial occlusive disease, cardiomyopathy,        heart failure, heart rhythm disorders, vascular restenosis,        and/or stroke;    -   reducing body weight or preventing an increase in body weight or        facilitating a reduction in body weight;    -   preventing, slowing, delaying or treating the degeneration of        pancreatic beta cells and/or the decline of the functionality of        pancreatic beta cells and/or for improving and/or restoring the        functionality of pancreatic beta cells and/or stimulating and/or        restoring the functionality of pancreatic insulin secretion;    -   preventing, slowing, delaying or treating non alcoholic fatty        liver disease (NAFLD) including hepatic steatosis, non-alcoholic        steatohepatitis (NASH) and/or liver fibrosis;    -   preventing, slowing the progression of, delaying or treating        type 2 diabetes with primary or secondary failure to        conventional (oral) antihyperglycemic mono- or combination        therapy;    -   achieving a reduction in the dose of conventional        antihyperglycemic medication required for adequate therapeutic        effect;    -   reducing the risk for adverse effects associated with        conventional antihyperglycemic medication; and/or    -   maintaining and/or improving the insulin sensitivity and/or for        treating or preventing hyperinsulinemia and/or insulin        resistance;    -   particularly in a patient with insufficient glycemic control        despite mono- or dual or triple combination therapy with        conventional oral or non-oral antidiabetic drug(s) selected from        metformin, sulphonylureas, thiazolidinediones (e.g.,        pioglitazone), glinides, alpha-glucosidase blockers, GLP-1 and        GLP-1 analogues, and insulin and insulin analogues.        Pharmaceutical Compositions

Methods by which to formulate compositions to target specific regions ofthe gastrointestinal tract, such as the colon, include, for example,release of drug in the gastrointestinal tract may be accomplished bychoosing a drug release controlling component to work together with somephysical, chemical or biochemical process in the gastrointestinal tract.A drug release controlling component may take advantage of processesand/or conditions within the gastrointestinal tract and in specificregions of the gastrointestinal tract such as, for example, osmoticpressure, hydrodynamic pressure, vapor pressure, mechanical action,hydration status, pH, bacterial flora, and enzymes.

Optionally, pharmaceutical compositions of the present disclosureincluding drug cores may further comprise a seal coating material thatseals the drug to prevent decomposition due to exposure to moisture,such as hydroxypropylmethylcellulose. Accordingly, the drug core of thepharmaceutical composition (containing the active agent) may first besealed with the seal coating material and then coated with the drugrelease controlling component to prevent decomposition of the activeagent by exposure to moisture. Seal coating materials include, in oneembodiment, acetyltributyl citrate, acetyltriethyl citrate, calciumcarbonate, carauba wax, cellulose acetate, cellulose acetate phthalate,cetyl alcohol, chitosan, ethylcellulose, fructose, gelatin, glycerin,glyceryl behenate, glyceryl palmitostearate, hydroxyethyl cellulose,hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose,hypromellose phthalate, isomalt, latex particles, maltitol,maltodextrin, methylcellulose, microcrystalline wax, paraffin,poloxamer, polydextrose, polyethylene glycol, polyvinyl acetatephthalate, polyvinyl alcohol, povidone, shellac, shellac with stearicacid, sodium carboxymethyl cellulose, sucrose, titanium oxide, tributylcitrate, triethyl citrate, vanillin, white wax, xylitol, yellow wax, andzein. Compositions of the present disclosure may also include filmforming agents, which include, for example, ammonium alginate, calciumcarbonate, chitosan, chlorpheniramine maleate, copovidone, dibutylphthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate,ethyl lactate, ethylcellulose, gelatin, hydroxyyethyl cellulose,hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate,maltodextrin, polydextrose, polyethylene glycol, polyethylene oxide,polymethylacrylates, poly(methylvinyl ether/maleic anhydride),polyvinylacetate phthalate, triethyl citrate, and vanillin. The amountof seal coating will vary in accordance with factors known by those ofskill in the art. The amount of seal coat is, in one embodiment about0.1% of the drug core, about 0.2% of the drug core, about 0.3% of thedrug core, about 0.4% of the drug core, about 0.5% of the drug core,about 0.6% of the drug core, about 0.7% of the drug core, about 0.8% ofthe drug core, about 0.9% of the drug core, about 1% w/w of the drugcore; about 2%, w/w of the drug core, about 3%, w/w, of the drug core,about 4%, w/w, of the drug core; about 5% w/w of the drug core; about6%, w/w of the drug core, about 7%, w/w, of the drug core, about 8%,w/w, of the drug core; about 9% w/w of the drug core; about 10%, w/w ofthe drug core, about 11%, w/w, of the drug core, about 12%, w/w, of thedrug core; about 14% w/w of the drug core; about 16%, w/w of the drugcore, about 18%, w/w, of the drug core, about 20%, w/w, of the drugcore; or more, if determined to be appropriate. Seal coats may also beapplied at amounts between about 1% and about 10% w/w of the drug core,between about 2% and 9% w/w of the drug core, between about 3% and 8%w/w of the drug core, between about 4% and 7% w/w of the drug core, andbetween about 5% and about 6% w/w of the drug core.

In one embodiment, drug release controlling components include, forexample, coatings, matrices, or physical changes. Coatings are used inone embodiment. Coatings include, for example, enteric coatings, timedelay coatings, bacterially degradable coatings, and mixtures thereof.The pharmaceutical composition may comprise multiple coatings of eitherthe same or different types of coatings. In choosing an appropriatecoating or mixture thereof, the formulations practitioner may consider anumber of variables influencing the location in which a drug will becomeavailable in the gastrointestinal tract, e.g., the pH at which coatingsdissolve; the time of dissolution (which is influenced by thickness ofthe coatings and/or additional components in the coatings); time oftransit through the gastrointestinal tract, and whether the coatings canbe degraded by the patent's digestive enzymes or require enzymes presentonly in bacteria residing in the lower intestine. As an example of acombination drug release controlling component is, for example, an innercore with two polymeric layers. The outer layer, an enteric coating, maybe chosen to dissolve at a pH level above 5. The inner layer, may bemade up of hydroxypropylmethylcellulose to act as a time delay componentto delay drug release for a predetermined period. The thickness of theinner layer can be adjusted to determine the lag time.

Methods by which skilled practitioners can assess where a drug isreleased in the gastrointestinal tract of patients are known in the art,and include scintigraphic studies, testing in biorelevant medium whichsimulates the fluid in relevant portions of the gastrointestinal tract,among others.

In certain embodiments, the active agent is released in, for example,the large intestine. In certain embodiments, the active agent isreleased in the large intestine in an amount selected from the groupconsisting of about 70%, about 75%, about 80%, about 85%, about 90%,about 95%, and about 100% w/w of the active agent present in theformulation. In certain embodiments, the active agent is released in thelarge intestine in an amount of about 80% to about 100% w/w of theactive agent present in the formulation.

In one embodiment, a drug release controlling component may include anenteric coating. The term “enteric coating” refers to a coating thatallows an active agent formulation to pass through the stomachsubstantially intact and subsequently disintegrate substantially in theintestines. In one embodiment, the disintegration occurs in the largeintestine.

In one embodiment, at least one active agent is incorporated into anerodible or non-erodible polymeric matrix controlled release device. Byan erodible matrix is meant aqueous-erodible or water-swellable oraqueous-soluble in the sense of being either erodible or swellable ordissolvable in pure water or requiring the presence of an acid or baseto ionize the polymeric matrix sufficiently to cause erosion ordissolution. When contacted with the aqueous environment of use, theerodible polymeric matrix imbibes water and forms an aqueous-swollen gelor “matrix” that entraps the solubility-improved form of the activeagent. The aqueous-swollen matrix gradually erodes, swells,disintegrates or dissolves in the environment of use, therebycontrolling the release of the active agent to the environment of use.The erodible polymeric matrix into which the active agent isincorporated may generally be described as a set of excipients that aremixed with the solubility-improved form following its formation that,when contacted with the aqueous environment of use imbibes water andforms a water-swollen gel or “matrix” that entraps the drug form. Drugrelease may occur by a variety of mechanisms: the matrix maydisintegrate or dissolve from around particles or granules of the drugin solubility-improved form; or the drug may dissolve in the imbibedaqueous solution and diffuse from the tablet, beads or granules of thedevice. A key ingredient of this water-swollen matrix is thewater-swellable, erodible, or soluble polymer, which may generally bedescribed as an osmopolymer, hydrogel or water-swellable polymer. Suchpolymers may be linear, branched, or crosslinked. They may behomopolymers or copolymers. Although they may be synthetic polymersderived from vinyl, acrylate, methacrylate, urethane, ester and oxidemonomers, they are most preferably derivatives of naturally occurringpolymers such as polysaccharides or proteins.

The term “cellulosic polymer” is used herein to denote a linear polymerof anhydroglucose. Cellulosic polymers that can be used advantageouslyin the present dosage forms include, without limitation,hydroxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose,hydroxypropyl methylcellulose, methylcellulose, ethylcellulose,cellulose acetate, cellulose acetate phthalate, cellulose acetatetrimellitate, hydroxypropyl methylcellulose phthalate,hydroxypropylcellulose phthalate, cellulose hexahydrophthalate,cellulose acetate hexahydrophthalate, carboxymethylcellulose,carboxymethylcellulose sodium, and microcrystalline cellulose. Preferredcellulosic polymers are alkyl-substituted cellulosic polymers thatultimately dissolve in the GI tract in a predictably delayed manner.Preferred alkyl-substituted cellulose derivatives are those substitutedwith alkyl groups of 1 to 3 carbon atoms each. Examples aremethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropyl methylcellulose, andcarboxymethylcellulose. In terms of their viscosities, one class ofpreferred alkyl-substituted celluloses includes those whose viscosity iswithin the range of about 50 to about 110,000 centipoise as a 2% aqueoussolution at 20° C. Another class includes those whose viscosity iswithin the range of about 800 to about 6,000 centipoise as a 1% aqueoussolution at 20° C. Particularly preferred alkyl-substituted cellulosesare hydroxyethylcellulose and hydroxypropylmethylcellulose. A presentlypreferred hydroxyethylcellulose is NATRASOL® 250HX NF (NationalFormulary), available from Aqualon Company, Wilmington, Del., USA.

Polyalkylene oxides are the preferred polymers herein, and thepolyalkylene oxides that are of greatest utility are those having theproperties described above for alkyl-substituted cellulose polymers. Aparticularly preferred polyalkylene oxide is poly(ethylene oxide), whichterm is used herein to denote a linear polymer of unsubstituted ethyleneoxide. Poly(ethylene oxide)s are often characterized by their viscosityin solution. For purposes of this disclosure, a preferred viscosityrange is about 50 to about 2,000,000 centipoise for a 2% aqueoussolution at 20° C. Preferred poly(ethylene oxide)s are those availablein the Polyox® family of trademarks, e.g., Polyox 303, Polyox Coag,Polyox 301, Polyox WSR N-60K, Polyox WSR 1105 and Polyox WSR N-80,having number average molecular weights of 7 million, 5 million, 4million, 2 million, 900,000 and 200,000, respectively, all products ofUnion Carbide Chemicals and Plastics Company Inc. of Danbury, Conn.,USA.

Polysaccharide gums, both natural and modified (semi-synthetic) can beused. Examples are dextran, xanthan gum, gellan gum, welan gum andrhamsan gum. Xanthan gum is preferred.

Crosslinked polyacrylic acids of greatest utility are those whoseproperties are the same as those described above for alkyl-substitutedcellulose and polyalkylene oxide polymers. Preferred crosslinkedpolyacrylic acids are those with a viscosity ranging from about 4,000 toabout 40,000 centipoise for a 1% aqueous solution at 25° C. Threepresently preferred examples are CARBOPOL® NF grades 971 P, 974P and934P (BF Goodrich Co., Specialty Polymers and Chemicals Div., Cleveland,Ohio, USA). Further examples are polymers known as WATER LOCK®, whichare starch/acrylates/acrylamide copolymers available from GrainProcessing Corporation, Muscatine, Iowa, USA.

Suitable polymers also include naturally occurring hydrophilic polymerssuch as, by way of example, proteins such as collagen, fibronectin,albumins, globulins, fibrinogen, fibrin and thrombin; aminatedpolysaccharides, particularly the glycosaminoglycans, e.g., hyaluronicacid, chitin, chondroitin sulfate A, B, or C, keratin sulfate,keratosulfate and heparin; guar gum; xanthan gum; carageenan; alginates;pectin; and activated polysaccharides such as dextran and starches.

The aforementioned list of polymers is not exhaustive, and a variety ofother synthetic hydrophilic polymers may be used, as will be appreciatedby those skilled in the art.

The polymer may include biodegradable segments and blocks, distributedeither throughout the polymer's molecular structure or present as asingle block, as in a block copolymer. Biodegradable segments are thosethat degrade so as to break covalent bonds. Typically, biodegradablesegments are segments that are hydrolyzed in the presence of water.Biodegradable segments may be composed of small molecular segments suchas ester linkages, anhydride linkages, ortho ester linkages, orthocarbonate linkages, amide linkages, phosphonate linkages, etc.

Any polymer or polymers of the matrix may also be crosslinked, with thedegree of crosslinking directly affecting the rate of polymer swellingas well as the erosion rate. That is, a polymer having a higher degreeof crosslinking will exhibit less swelling and slower erosion than apolymer having a lower degree of crosslinking. Crosslinked polymers maybe prepared using the above-mentioned exemplary polymers usingconventional crosslinking procedures (e.g., chemical crosslinking withan added crosslinking agent, photolytically induced crosslinking, etc.),or the polymers may be obtained commercially in crosslinked form.

The water-swellable polymers can be used individually or in combination.Certain combinations will often provide a more controlled release of thedrug than their components when used individually. Examples include, butare not limited to, the following: a cellulosic polymer combined with agum, such as hydroxyethylcellulose or hydroxypropylcellulose combinedwith xanthan gum; a polyalkylene oxide combined with a gum, such aspoly(ethylene oxide) combined with xanthan gum; and a polyalkylene oxidecombined with a cellulosic polymer, such as poly(ethylene oxide)combined with hydroxyethylcellulose or hydroxypropylcellulose.

Combinations of different poly(ethylene oxide)s are also contemplated,with polymers of different molecular weights contributing to differentdosage form characteristics. For example, a very high molecular weightpoly(ethylene oxide) such as Polyox 303 (with a number average molecularweight of 7 million) or Polyox Coag (with a number average molecularweight of 5 million) may be used to significantly enhance diffusionrelative to disintegration release by providing high swelling as well astablet integrity. Incorporating a lower molecular weight poly(ethyleneoxide) such as Polyox WSR N-60K (number average molecular weightapproximately 2 million) with Polyox 303 and/or Polyox Coag increasesdisintegration rate relative to diffusion rate, as the lower molecularweight polymer reduces swelling and acts as an effective tabletdisintegrant. Incorporating an even lower molecular weight poly(ethyleneoxide) such as Polyox WSR N-80 (number average molecular weightapproximately 200,000) further increases disintegration rate.

The hydrophilicity and water swellability of these polymers cause thedrug-containing matrices to swell in size in the gastric cavity due toingress of water in order to achieve a size that will be retained in thestomach when introduced during the fed mode. These qualities also causethe matrices to become slippery, which provides resistance toperistalsis and further promotes their retention in the stomach. Therelease rate of a drug from the matrix is primarily dependent upon therate of water imbibition and the rate at which the drug dissolves anddiffuses from the swollen polymer, which in turn is related to thesolubility and dissolution rate of the drug, the drug particle size andthe drug concentration in the matrix.

The amount of polymer relative to the drug can vary, depending on thedrug release rate desired and on the polymer, its molecular weight, andexcipients that may be present in the formulation. The amount of polymerwill be sufficient however to retain at least about 40% of the drugwithin the matrix one hour after ingestion (or immersion in the gastricfluid). Preferably, the amount of polymer is such that at least 50% ofthe drug remains in the matrix one hour after ingestion. Morepreferably, at least 60%, and most preferably at least 80%, of the drugremains in the matrix one hour after ingestion. In all cases, however,substantially all of the drug will be released from the matrix withinabout eight hours, and preferably within about six hours, afteringestion, “substantially all” meaning at least 85%, preferably at least90%. In general, it will be appreciated that the matrix will delivergreater than about 80% of the active agent, preferably at least 85%,preferably greater than 90%, preferably more than 95%, and in certainembodiments 100% of the active agent over a time period in the range ofabout for example, two to eight hours as determined in vitro using USPdisintegration test equipment.

It has now been found that higher molecular weight polymers arepreferred to provide a desired extended release profile using thepresent dosage forms. Suitable molecular weights are generally in therange of about 5,000 to about 20,000,000. For sparingly soluble drugs,the polymers have molecular weights preferably in the range of about5,000 to about 8,000,000, more preferably in the range of about 10,000to about 5,000,000. For water-soluble drugs, the polymers preferablyhave molecular weights of at least about 10,000, but the molecularweight used will vary with the selected polymer. For example, forhydroxypropyl methylcellulose, the minimum molecular weight may be aslow as 10,000, while for poly(ethylene oxide)s the molecular weight maybe far higher, on the order of 2,000,000 or more.

The benefits of this disclosure will be achieved over a wide range ofdrug loadings, with the weight ratio of drug to polymer generally,although not necessarily, ranging from 1:1000 to about 85:15, typicallyfrom 1:500 to about 85:15, more typically from 1:400 to about 80:20.Preferred loadings (expressed in terms of the weight percent of drugrelative to total of drug and polymer) are those within the range ofapproximately 10% to 80%, more preferably within the range ofapproximately 30% to 80%, and most preferably, in certain cases, withinthe range of approximately 30% to 70%. For some applications, however,the benefits will be obtained with drug loadings as low as 0.01%, as maybe inferred from the aforementioned ratios.

Such materials include naturally occurring polysaccharides such aschitin, chitosan, dextran and pullulan; gum agar, gum arabic, gumkaraya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guargum, xanthan gum and scleroglucan; starches such as dextrin andmaltodextrin; hydrophilic colloids such as pectin; phosphatides such aslecithin; alginates such as ammonium alginate, sodium, potassium orcalcium alginate, propylene glycol alginate; gelatin; collagen; andcellulosics. By “cellulosics” is meant a cellulose polymer that has beenmodified by reaction of at least a portion of the hydroxyl groups on thesaccharide repeat units with a compound to form an ester-linked or anether-linked substituent. For example, the cellulosic ethyl cellulosehas an ether linked ethyl substituent attached to the saccharide repeatunit, while the cellulosic cellulose acetate has an ester linked acetatesubstituent.

A preferred class of cellulosics for the erodible matrix comprisesaqueous-soluble and aqueous-erodible cellulosics such as ethyl cellulose(EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC). Aparticularly preferred class of such cellulosics comprises variousgrades of low viscosity (MW less than or equal to 50,000 daltons) andhigh viscosity (MW greater than 50,000 daltons) HPMC. Commerciallyavailable low viscosity HPMC polymers include the Dow METHOCEL seriesE5, E5LV, E15LV, E50LV, E50SLV, and K100LY, while high viscosity HPMCpolymers include E4MCR, E10MCR, K4M, K15M and K100M; especiallypreferred in this group are the METHOCEL K series. Other commerciallyavailable types of HPMC include the Shin Etsu METOLOSE 90SH series.

Other materials useful as the erodible matrix material include, but arenot limited to, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol,polyvinyl acetate, glycerol fatty acid esters, polyacrylamide,polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid(EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.) and other acrylic acidderivatives such as homopolymers and copolymers of butylmethacrylate,methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.

The erodible matrix polymer may contain a wide variety of the same typesof additives and excipients known in the pharmaceutical arts, includingosmopolymers, osmagens, solubility-enhancing or -retarding agents andexcipients that promote stability or processing of the device. Incertain embodiments, the at least one erodible matrix material ispresent in a concentration of about 5% to about 15% w/w of the core. Incertain embodiments, the at least one erodible matrix material ispresent in a concentration of about 1% to about 30% w/w of the core. Incertain embodiments, the at least one erodible matrix material ispresent in a concentration of about 2% to about 25% w/w of the core. Incertain embodiments, the at least one erodible matrix material ispresent in a concentration of about 3% to about 20% w/w of the core. Incertain embodiments, the at least one erodible matrix material ispresent in a concentration of about 10% to about 25% w/w of the core. Incertain embodiments, the at least one erodible matrix material ispresent in a concentration of about 15% to about 25% w/w of the core. Incertain embodiments, the at least one erodible matrix material ispresent in a concentration of about 20% to about 40% w/w of the core. Incertain embodiments, the at least one erodible matrix material ispresent in a concentration of about 21% to about 38% w/w of the core. Incertain embodiments, the at least one erodible matrix material ispresent in a concentration of about 8% to about 13% w/w of the core. Incertain embodiments, the at least one erodible matrix material ispresent in a concentration of about 12.12% w/w of the core. In exemplaryembodiments, formulations of the disclosure may comprise erodible matrixmaterial at a concentration of about 0.1%, about 0.2%, about 0.3%, about0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%,about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%,about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%,about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about75%, about 75%, and about 80% of the formulation, such as the core.

The formulation may comprise an excipient that is a swellable materialsuch as a hydrogel in amounts that can swell and expand. Examples ofswellable materials include polyethylene oxide, hydrophilic polymersthat are lightly cross-linked, such cross-links being formed by covalentor ionic bond, which interact with water and aqueous biological fluidsand swell or expand to some equilibrium state. Swellable materials suchas hydrogels exhibit the ability to swell in water and retain asignificant fraction of water within its structure, and whencross-linked they will not dissolve in the water. Swellable polymers canswell or expand to a very high degree, exhibiting a 2 to 50 fold volumeincrease. Specific examples of hydrophilic polymeric materials includepoly(hydroxyalkyl methacrylate), poly(N-vinyl-2-pyrrolidone), anionicand cationic hydrogels, polyelectrolyte complexes, poly(vinyl alcohol)having a low acetate residual and cross-linked with glyoxal,formaldehyde, or glutaraldehyde, methyl cellulose cross-linked withdialdehyde, a mixture of cross-linked agar and carboxymethyl cellulose,a water insoluble, water-swellable copolymer produced by forming adispersion of finely divided copolymer of maleic anhydride with styrene,ethylene, propylene, butylene, or isobutylene cross-linked with from0.001 to about 0.5 moles of a polyunsaturated cross-linking agent permole of maleic anhydride in the copolymer, water-swellable polymers ofN-vinyl lactams, cross-linked polyethylene oxides, and the like. Otherexamples of swellable materials include hydrogels exhibiting across-linking of 0.05 to 60%, hydrophilic hydrogels known as Carbopolacidic carboxy polymer, Cyanamer™ polyacrylamides, cross-linkedwater-swellable indene-maleic anhydride polymers, Good-rite™ polyacrylicacid, starch graft copolymers, Aqua-Keeps.™ acrylate polymer, diestercross-linked polyglucan, and the like.

The formulations may comprise additives such as polyethylene oxidepolymers, polyethylene glycol polymers, cellulose ether polymers,cellulose ester polymers, homo- and copolymers of acrylic acidcross-linked with a polyalkenyl polyether, poly(meth)acrylates,homopolyers (e.g., polymers of acrylic acid crosslinked with allylsucrose or allyl pentaerythritol), copolymers (e.g., polymers of acrylicacid and C₁₀-C₃₀ alkyl acrylate crosslinked with allyl pentaerythritol),interpolymers (e.g., a homopolymer or copolymer that contains a blockcopolymer of polyethylene glycol and a long chain alkyl acid ester),disintegrants, ion exchange resins, polymers reactive to intestinalbacterial flora (e.g., polysaccharides such as guar gum, inulin obtainedfrom plant or chitosan and chondrotin sulphate obtained from animals oralginates from algae or dextran from microbial origin) andpharmaceutical resins.

A non-limiting list of suitable sustained-release materials which may beincluded in a sustained-release matrix according to the disclosureincludes hydrophilic and/or hydrophobic materials, such as gums,cellulose ethers, acrylic resins, protein derived materials, waxes,shellac, and oils such as hydrogenated castor oil and hydrogenatedvegetable oil. However, any pharmaceutically acceptable hydrophobic orhydrophilic sustained-release material which is capable of impartingsustained-release of the API may be used in accordance with thecompositions and methods of the disclosure. Preferred sustained-releasepolymers include alkylcelluloses such as ethylcellulose, acrylic andmethacrylic acid polymers and copolymers; and cellulose ethers,especially hydroxyalkylcelluloses (especiallyhydroxypropylmethylcellulose) and carboxyalkylcelluloses. Preferredacrylic and methacrylic acid polymers and copolymers include methylmethacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates,ethyl acrylate, trimethyl ammonioethyl methacrylate, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methylmethacrylate), poly(methacrylic acid) (anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. Certain preferred embodiments utilizemixtures of any of the foregoing sustained-release materials in thematrix of the disclosure. The matrix also may include a binder.

In addition to the above ingredients, a sustained-release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids and glidants that are conventionalin the pharmaceutical art.

A sustained-release matrix can be prepared by, e.g., melt-granulation ormelt-extrusion techniques. Generally, melt-granulation techniquesinvolve melting a normally solid hydrophobic binder material, e.g., awax, and incorporating a powdered drug therein. To obtain a sustainedrelease dosage form, it may be necessary to incorporate a hydrophobicsustained-release material, e.g., ethylcellulose or a water-insolubleacrylic polymer, into the molten wax hydrophobic binder material.

Colon Specific Drug Delivery

The approaches for colon specific drug delivery system are prodrug orcoated or matrix preparation.

The Commonly Used Approaches are:

1. pH dependent

2. Time dependent

3. Pressure dependent

4. Bacteria dependent

pH Dependent Delivery:

The change in the pH along the gastrointestinal tract has been used as amean for colon targeted drug delivery. This can be achieved by means ofcoating that are intact at lower pH of the stomach but that willdissolved at neutral pH of the colon. The pH in the gastrointestinaltract varies from 1.2 in the stomach, 6.6 in the proximal smallintestine and about 7.5 in the distal part of small intestine. This pHvariation CSDDS in the stomach and small intestine has previously beenused to deliver drugs to small intestine by way of pH sensitive entericcoating. These polymer coats are recalcitrant to the acidic condition ofthe stomach but ionize and get dissolved above a certain thresholdalkaline pH found in small intestine. Thus it is possible to apply sameconcept to deliver drugs to the terminal of ileum or colon by use ofenteric polymers with a relatively high threshold pH for dissolution andsubsequent drug release.

The most commonly used polymer for this purpose is methacrylic acid andmethylmathacrylate that dissolve at pH 6 (Eudragit L) and pH 7 (EudragitS) have been investigated. This approach is based on the fact that thegastrointestinal pH is increase progressively from small intestine tocolon. But the pH of the distal is 6. This delivery system thus has ainclination to release the drug load prior to reaching the colon. Toovercome the problem of premature drug release, a copolymer ofmethacrylic acid, methyl methacrylate and ethyl acrylate (Eudragit FS)which dissolve at slower rate and at higher threshold pH 7 to 7.5 wasreported. The gamma scintigraphic study comparing the in vivoperformance of these various polymers revealed that Eudragit FS (coatedon tablet) was superior as compare to Eudragit L and S polymers in theterms of drug release retardation in the small intestine. That is theintrasubject variability to this polymer is apparent.

Time Dependent Delivery:

The average transit time in the stomach is 2 hr which may vary, while inthe small intestine it is relatively constant around 3 hr. The typicaltransit time varies from 20 to 30 h. Time dependent drug delivery systemallow the drug release after a set time delay. For the colon targeteddrug release the lag time should similar to the time taken for thesystem to reach the colon. The lag time of 5 hr is usually consideredsufficient on the basis of relatively constant transit time in the smallintestine (3 hr); Pulsicap was the first formulation developed based onthis approach.Sinha V R and Kumaria R. demonstrated use of shellac,Eudragit L100 and ethylcellulose at various thicknesses for colontargeted drug delivery of a drug and out of this shellac showedpromising result. Time dependent approach was also been used forchronopharmacotherapy using nifedipine and coating with polyethyleneoxide-polyethylene glycol mixtures which release the drug in colon.Eudragit L100 along with channeling agent like sodium chloride has beeneffectively confirmed for achieving colon target drug delivery based onthis approach. Hydroxy propyl methyl cellulose has been used for colonspecific drug delivery of pseudoephedrine HCL using this approach.Hydroxy propyl ethyl cellulose, Hydroxy propyl methyl cellulose acetatesuccinate were also been used for time dependent colon specific drugdelivery. HPMC along with pectin has also been shown to producepromising result for colon drug delivery system for sennosides which isused as an herbal purgative. The hydrogel based capsule was reportedwhich swells after CSDDS definite time and allow drug release after lagtime successfully in colon, hence by modifying hydrogel composition andsize, lag time could be varied.

Combination of Time and pH Dependent:

Due to variations in pH and gastric transit time colon drug deliverybased only on pH and time would not be consistent. Thereforeformulations have been developed base on combination of pH uniqueness ofdifferent polymers and transit time in the small intestine usingEudragit FS30D and Eudragit RL-RS32. Pulsatile device in the form ofcapsule has been developed using this approach for chronopharmacologyfor better treatment of nocturnal asthma, for example, KrishnamachariY., et. al. developed a controlled release microparticles of budesonideusing poly (dl-lactide-co-glycoside) and Eudragit S-100 based on thecombinational Crohn's disease treatment.

Diclofenac sodium and 5-amino salicylic acid pellets were coated withethylcellulose and methacrylic acid copolymers respectively and in vivostudies using dogs shows promising result of colon targeting followingoral administration. Akhgari A., et al, demonstrated combination use ofEudragit S100 and L100 along with Eudragit RS as a single layer coatingon pellet for colon targeted drug delivery.

Pressure Dependent Drug Delivery:—

The muscular contraction of the gut generate pressure for grinding andpropulsion of intestinal contents, this pressure is vary all the wayCSDDS through the gastrointestinal tract, luminal pressure in the colonhigher due to the process of stool formation. The pressure controlleddelivery consists of drug dispersed in a suppository base, coated withthe hydrophobic polymer. On swallowing body temperature causes themelting of suppository base and subsequent increases in volume of thesystem. The balloon doesn't get rupture in the luminal pressure of thesmall intestine resulting from muscular contraction, but will rupturewhen in the colon due to more intense pressure of the contractions ofthe colon and contents of higher viscosity. Co-administered food mayaffect the performance of system based on pressure, as fed statecontraction may be adequately influential to disintegrate the capsule inthe stomach. The empty pressure-controlled colon delivery capsules weredeveloped by a dipping method where the inner coat was water-insolublepolymer membrane like ethylcellulose and the outer one washydroxypropylmethylcellulose phthalate, an enteric polymer membrane.

Bacteria Dependent Drug Delivery:

Drug can be administered locally and selectively to the colon if theyare enclosed in an azo-aromatic cross-linked polymer subject to cleavageby azoreductase of the colonic microflora. This approach of coating adrug with biodegradable material for the colon targeting was reportedfor used large amount of the drug. The drug release rate is dependent onof the bacterial enzymes activity in the colon rather than on that ofthe host. The total bacterial count in colon is reported to be 1011 pergram as CSDDS compared to 104 per gram in upper part of gastrointestinaltract, 400 different anaerobic species are present. Azo bond basedpolymer for the obtaining universal carrier systems was reported but thesafety and toxicity of these synthetic polymers need to be considered.Natural materials, fundamentally those that are polysaccharide-based,offer a workable alternative to safety problem, material includeschitosan, amylose, dextran, guar gum, insulin, pectin. Biodegradablepolymers degrade in vivo, either in presence of enzyme ornonenzymatically, to produce products which are nontoxic andbiocompatible. The microflora composition remains relatively constantacross a diverse human population. Amylose one of the polysaccharideobtained from starch shown potential of colonic drug delivery due todegradation of amylase by enzyme amylase in colon. 38. Similarly pectinalong with ethylcellulose was reported for colon specific drug deliveryof 5-flurouracil. The drug sulfasalazin (SAS) used for IBD40 andrheumatoid arthritis is the earliest example of targeted drug deliveryin the colon based on this approach. Only 12% drug was released in thesmall intestine after oral administration. When SAS reaches the colonafter oral administration the diazoreductase bacteria of colon bacteriacleaves the azo bond releasing 5-amino salicylic acid and sulfapyuridineinto colon lumen.

Osalazine consist of 5-amino salicylic acid linked by an azo bond wasdeveloped to directly deliver 5-amino salicylic acid to the colon.Balsalzide is another prodrug i.e. reported to benefit from a less toxicCSDDS carrier molecule than in SAS. Balasalazide is 5-amino salicylicacid linked by a diazo moiety to 4-amino benzoyl-β-alanine. A comparabletotal release of 5-amino salicylic acid in rats has been observed fromSAS and 5-amino salicylic acid in rat azo linked to polymeric prodrugconsisting of polysulfonamidoethylene as a carrier molecule (Polyasa).The prodrug approach has been used where naproxen was conjugated todextran by an ester linkage. The release of naproxen was higher in thepig caecum and colon homogenates as compare to small intestine.Chitosan, a polysaccharide has been used for colon targeted drugdelivery in several dosage forms including, matrices, hydrogel,microspheres and now recently in osmotic pump. Laroyl and crosslinkedgalactomannan45Cyclodextrins an oligosaccharides46.dextran and aminoacid conjugates were successfully reported for colonic drug deliverymight be influenced by many factors including diet, drugs, andgastrointestinal diseases may influence the metabolic activities ofwhich should be considered while designing of colon targeted drugdelivery system based on this approach.

Combination Therapies

One or more additional agents, such as antipruritic agents, canoptionally be used in combination with the active agent of thecompositions and methods of the disclosure to treat pruritus (includingacute and chronic pruritus). Examples of antipruritic agents includewithout limitation:

antihistamines, including but not limited to antihistamines that inhibitaction at the histamine H.sub.1 receptor (e.g., acrivastine, antazoline,azelastine, bilastine, brompheniramine, buclizine, bromodiphenhydramine,carbinoxamine, cetirizine, chlorpromazine, cyclizine, chlorpheniramine,chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine,dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimetindene,diphenhydramine, doxepin, doxylamine, ebastine, embramine, fexofenadine,hydroxyzine, levocetirizine, loratadine, meclozine, mepyramine,mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine,phenyltoloxamine, promethazine, pyrilamine, quetiapine, rupatadine,tripelennamine and triprolidine), and antihistamines that inhibit actionat the histamine H.sub.4 receptor (e.g., thioperamide, JNJ 7777120 andVUF-6002), and analogs and derivatives thereof; serotonin receptorantagonists, including but not limited to 5-HT2 antagonists (e.g.,clozapine, cyproheptadine, ketanserin, pizotifen and quetiapine) and5-HT3 antagonists (e.g., alosetron, cilansetron, dolasetron,granisetron, ondansetron, palonosetron and tropisetron), and analogs andderivatives thereof;

neurokinin-1 (NK-1) receptor antagonists, including but not limited toaprepitant, casopitant (GW679769), dapitant, ezlopitant, fosaprepitant,lanepitant (LY-303870), maropitant, netupitant, nolpitant, orvepitant,rolapitant, vestipitant, vofopitant, AV-818, BIIF 1149CL, CP122,721,DNK-333, GSK-424887, L-733060, L-759274, LY-686017, M516102 and TA-5538,and analogs and derivatives thereof;

opioid receptor antagonists, including but not limited to butorphanol,cyprodime, levallorphan (lorfan or naloxiphan), nalbuphine, nalorphine(lethidrone or nalline), naloxone, naloxol, nalmefene, naltrexone (e.g.,naltrexone 1% cream) and naltrexol, and analogs and derivatives thereof;

opioid receptor agonists, including but not limited to selective kappaopioid receptor agonists (e.g., asimadoline, bremazocine, dynorphin,enadoline, ketazocine, nalfurafine, salvinorin A, 2-methoxymethylsalvinorin B, 2-ethoxymethyl salvinorin B, 2-fluoroethoxymethylsalvinorin B, spiradoline, tifluadom, BRL-52537, FE 200665, GR-89696,HZ-2, ICI-199,441, ICI-204,448, LPK-26, U-50488 and U-69,593), andanalogs and derivatives thereof;

Janus kinase (JAK) inhibitors, including but not limited to JAK1inhibitors (e.g., GLPG0634 and GSK2586184), JAK2 inhibitors (e.g.,lestaurtinib, pacritinib, CYT387 and TG101348), JAKI/JAK2 inhibitors(e.g., baricitinib and ruxolitinib), and JAK3 inhibitors (e.g.,tofacitinib), and analogs and derivatives thereof;

immunomodulators and immunosuppressants, including but not limited tothalidomide, antimetabolites (e.g., antifolates such as methotrexate),and calcineurin inhibitors (e.g., ciclosporin [cyclosporin],pimecrolimus and tacrolimus), and analogs and derivatives thereof;antidepressants, including but not limited to tricyclic antidepressants(e.g., amitriptyline, amitriptylinoxide, amoxapine, dosulepin[dothiepin], doxepin and melitracen), tetracyclic antidepressants (e.g.,amoxapine, maprotiline, mazindol, mianserin, mirtazapine andsetiptiline), selective serotonin reuptake inhibitors (SSRIs, e.g.,citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine,paroxetine and sertraline), and serotonin-norepinephrine reuptakeinhibitors (SNRIs, e.g., bicifadine, duloxetine, milnacipran,levomilnacipran, sibutramine, venlafaxine, desvenlafaxine andSEP-227162), and analogs and derivatives thereof; anticonvulsants,including but not limited to carbamazepine, gabapentin, pregabalin, andvalproic acid and salts thereof (e.g., sodium valproate), and analogsand derivatives thereof;

corticosteroids, including but not limited to hydrocortisone types(e.g., cortisone and derivatives thereof [e.g., cortisone acetate],hydrocortisone and derivatives thereof [e.g., hydrocortisone acetate,hydrocortisone-17-aceponate, hydrocortisone-17-buteprate,hydrocortisone-17-butyrate and hydrocortisone-17-valerate],prednisolone, methylprednisolone and derivatives thereof [e.g.,methylprednisolone aceponate], prednisone, and tixocortol andderivatives thereof [e.g., tixocortol pivalate]), betamethasone types(e.g., betamethasone and derivatives thereof [e.g., betamethasonedipropionate, betamethasone sodium phosphate and betamethasonevalerate], dexamethasone and derivatives thereof [e.g., dexamethasonesodium phosphate], and fluocortolone and derivatives thereof [e.g.,fluocortolone caproate and fluocortolone pivalate]), halogenatedsteroids (e.g., alclometasone and derivatives thereof [e.g.,alclometasone dipropionate], beclometasone and derivatives thereof[e.g., beclometasone dipropionate], clobetasol and derivatives thereof[e.g., clobetasol-17-propionate], clobetasone and derivatives thereof[e.g., clobetasone-17-butyrate], desoximetasone and derivatives thereof[e.g., desoximetasone acetate], diflorasone and derivatives thereof[e.g., diflorasone diacetate], diflucortolone and derivatives thereof[e.g., diflucortolone valerate], fluprednidene and derivatives thereof[e.g., fluprednidene acetate], fluticasone and derivatives thereof[e.g., fluticasone propionate], halobetasol [ulobetasol] and derivativesthereof [e.g., halobetasol proprionate], halometasone and derivativesthereof [e.g., halometasone acetate], and mometasone and derivativesthereof [e.g., mometasone furoate]), acetonides and related substances(e.g., amcinonide, budesonide, ciclesonide, desonide, fluocinonide,fluocinolone acetonide, flurandrenolide [flurandrenolone orfludroxycortide], halcinonide, triamcinolone acetonide and triamcinolonealcohol), and carbonates (e.g., prednicarbate), and analogs andderivatives thereof; local anesthetics, including but not limited toamides (e.g., articaine, bupivacaine, cinchocaine [dibucaine],etidocaine, levobupivacaine, lidocaine [e.g., lidocaine 2.5-5% cream],prilocaine [e.g., prilocaine 2.5% cream], EMLA [lidocaine2.5%/prilocaine 2.5% cream], mepivacaine, ropivacaine and trimecaine),esters (e.g., benzocaine, chloroprocaine, cocaine, cyclomethycaine,dimethocaine [larocaine], piperocaine, procaine [novocaine],proparacaine, propoxycaine, stovaine and tetracaine [amethocaine]),ethers (e.g., polidocanol [e.g., polidocanol 3% foam] and pramocaine[pramoxine] [e.g., pramoxine 1% cream]), and naturally derived localanesthetics (e.g., cocaine, eugenol, menthol, saxitoxin, neosaxitoxinand tetrodotoxin), and analogs and derivatives thereof; counterirritantsand cooling agents, including but not limited to capsaicin, camphor,mint oil, menthol (e.g., menthol 1-3% cream), and phenol (e.g., incalamine lotion), and analogs and derivatives thereof; moisturizers,including but not limited to aqueous moisturizers, low pH moisturizerscontaining an acid (e.g., lactic acid), and moisturizers containing ahumectant that attracts and retains water (e.g., glycerol, sorbitol,lactate, urea, and hyaluronic acid and salts thereof), an occlusive thatprevents evaporation {e.g., oils (e.g., mineral oil and silicone oil[e.g., dimethicone]) and petroleum jelly (petrolatum)}, and/or anemollient that provides partial hydration and occlusion (e.g., oils,waxes [e.g., lanolin and paraffin], lipids [e.g., phospholipids,ceramides, triglycerides, glycol stearate, glyceryl stearate, fattyacids and squalene], and sterols [e.g., cholesterol and phytosterol]),and analogs and derivatives thereof; and other kinds of antipruriticagents, including but not limited to S-adenosyl methionine, botulinumtoxin (e.g., botulinum toxin types A and B), vitamin D and analogs andderivatives thereof (e.g., calcitriol and calcipotriol [calcipotriene]),non-steroidal anti-inflammatory drugs (NSAIDs, e.g., aspirin),cannabinoid receptor agonists (e.g., CB.sub.2 agonists, such aspalmitoylethanolamide), inhibitors of cytokines (e.g., antibodies tointerleukins, such as IL-31), antagonists of the prostaglandin 0.sub.2receptor (DP.sub.1) and/or the chemoattractant receptor homologousmolecule expressed on TH.sub.2 cells (CRTH2) (e.g., TS-022),phosphodiesterase (PDE) inhibitors (e.g., PDE4 inhibitors, such asapremilast), protease-activated receptor 2 (PAR2) antagonists (e.g.,GB83), transient receptor potential vanilloid (TRPV) antagonists (e.g.,TRPV1 antagonists, such as capsazepine and SB-705498), inhibitors ofneurotrophic tyrosine kinase receptors (e.g., TrkA inhibitors, such asCT327), antimicrobials (including antibiotics, antifungals, antiviralsand antiparasitics, such as crotamiton and rifampin [rifampicin]), bileabsorption-reducing or bile sequestering agents (e.g., ursodeoxycholicacid [ursodiol]), ultraviolet radiation (e.g., ultraviolet A and B), andtherapeutic agents that treat the underlying causes of thepruritus-associated conditions, and analogs and derivatives thereof.

If desired (e.g., for relief from pruritus during the day), anon-sedating antipruritic agent can be used. For example,second-generation and third-generation antihistamines are designed to benon-sedating, or less sedating than first-generation antihistamines.Non-limiting examples of second-generation and third-generationantihistamines include acrivastine, astemizole, azelastine, bepotastine,bilastine, cetirizine, levocetirizine, ebastine, fexofenadine,ketotifen, levocabastine, loratadine, desloratadine, mizolastine,olopatadine, quifenadine, rupatadine and terfenadine.

The optional additional antipruritic agent(s) can be administered to asubject suffering from pruritus concurrently with (e.g., in the samecomposition as the active agent of the disclosure or in separatecompositions) or sequentially to (before or after) administration of theactive agent of the disclosure. The active agent of the compositions andmethods of the disclosure and the optional additional antipruriticagent(s) independently can be administered in any suitable mode,including without limitation orally, topically (e.g.,dermally/epicutaneously, transdermally, mucosally, transmucosally,intranasally [e.g., by nasal spray or drop], opthalmically [e.g., by eyedrop], pulmonarily [e.g., by inhalation], bucally, sublingually,rectally and vaginally), by injection or infusion (e.g., parenterally,including intramuscularly, subcutaneously, intradermally,intravenously/intravascularly, and intrathecally), and by implantation(e.g., subcutaneously and intramuscularly). In some embodiments, anantipruritic agent is administered topically (e.g., dermally) if thepruritus is localized, and is administered systemically (e.g., orally orintravenously) if the pruritus is widespread (generalized) or has asystemic cause. In certain embodiments, active agent of the disclosureand/or the optional additional antipruritic agent(s) are administeredorally. In other embodiments, active agent of the disclosure and/or theoptional additional antipruritic agent(s) are administered topically(e.g., dermally, mucosally, bucally or sublingually).

The active agents of the disclosure and the optional additionalagent(s), such as antipruritic agents, independently can be administeredin any suitable frequency, including without limitation daily (one, two,three or more times per day), every two days, twice weekly, thriceweekly, weekly, every two weeks, every three weeks, monthly, every twomonths and every three months. The dosing frequency can depend on, e.g.,the mode of administration chosen. For example, a dermal formulation ofactive agent of the disclosure, and/or that of the optional additionalantipruritic agent(s), can be applied to the skin of a subject two,three or four times a day. In some embodiments, active agent of thedisclosure is administered under a chronic dosing regimen. In certainembodiments, active agent of the disclosure is administered over aperiod of at least 2 weeks, 3 weeks, 1 month, 1.5 months, 2 months, 3months, 4 months, 5 months, 6 months or longer.

Coating

The coating of pH-sensitive (enteric) polymers to tablets, capsules andother oral formulations of the present disclosure provided delayedrelease and protect the active drug from gastric fluid. In general,enteric coatings should be able to withstand the lower pH values of thestomach and small intestine and be able to disintegrate at the neutralor slightly alkaline pH of the large intestine. Enteric coatings are awell-known class of compounds. Coating pharmaceutically activecompositions with enteric coatings is well known in the art to enablepharmaceutical compositions to bypass the stomach and its low acidity.Enteric coatings generally refer to a class of compounds that dissolveat or above a particular pH and include a number of pH-sensitivepolymers. The pH dependent coating polymer may be selected from thoseenteric coatings known to those skilled in the art. Such polymers may beone or more of the group comprising hydroxypropylmethylcellulosephthalate, polyvinyl acetate phthalate (PVAP),hydroxypropylmethylcellulose acetate succinate (HPMCAS), alginate,carbomer, carboxymethyl cellulose, methacrylic acid copolymer (such as,for example, a cationic copolymer of dimethyl aminoethyl methacrylateand neutral methacrylic esters), polyvinyl acetate phthalate, celluloseacetate trimellitate, shellac, cellulose acetate phthalate (CAP), starchglycolate, polacrylin, methyl cellulose acetate phthalate,hydroxymethylcellulose phthalate, hydroxymethylmethylcellulose acetatesuccinate, hydroxypropylcellulose acetate phthalate, cellulose acetateterephthalate, cellulose acetate isophthalate, and includes the variousgrades of each polymer such as HPMCAS-LF, HPMCAS-MF and HPMCAS-HG, ormixtures thereof. Other enteric coatings suitable for the presentdisclosure include acetyltributyl citrate, carbomers, guar gum,hypromellose acetate succinate, hypromellose phthalate,polymethacrylates, tributyl citrate, triethyl citrate, white wax, andzein.

In one embodiment, the pH dependent coating is selected from the groupconsisting of methacrylic acid copolymers of varying threshold pH (suchas, but not limited to EUDRAGIT S 100 (a cationic copolymer of dimethylaminoethyl methacrylate and neutral methacrylic acid esters manufacturedby Rohm Pharma GmbH of Darmstadt, Germany)).

Multiple coatings of enteric polymers may be utilized. In oneembodiment, the first coating (closest to the core) is an entericcoating that will survive until the dosage form arrives at the largeintestine/colon. To target the large intestine, in one embodiment anenteric coating comprises a series of methacrylic acid anioniccopolymers known as EUDRAGIT S. The EUDRAGIT S films are colorless,transparent and brittle. In one embodiment, the enteric coatingcomprises EUDRAGIT S100. The EUDRAGIT S coatings are insoluble in purewater, in buffer solutions below a pH of 6.0 and also in natural andartificial gastric juices. They are slowly soluble in the region of thedigestive tract where the juices are neutral to weakly alkaline (i.e.,the large intestine and the colon) and in buffer solutions above a pH of7.0. Mixtures of these various enteric polymers recited above, can beused in the present disclosure. Further, the use of plasticizers isincluded in one embodiment with the enteric polymer coatings usefulherein.

The disintegration rates of enteric coated tablets are dependent on thepolymer combination used to coat the tablets, the pH of thedisintegration media, and the coating level of the tablets (i.e.,thickness of the coating). The presence of plasticizer and the nature ofthe salts in the dissolution medium also influence the dissolution rate.

The enteric coating may also be modified through the inclusion of anedible acid to retard or slow the dissolution of the coating in theintestines. Any edible acid may be used. Representative edible acidsinclude acetic acid, benzoic acid, fumaric acid, sorbic acid, propionicacid, hydrochloric acid, citric acid, malic acid, tartaric acid,isocitric acid, oxalic acid, lactic acid, the phosphoric acids andmixtures thereof. One embodiment includes fumaric acid and malic acids.The weight percent of the edible acid in the enteric coating solution(polymer, plasticizer, anti-tack agents, water and the like) can rangefrom about 5 to about 40%, with 10 to 30% present in one embodiment and10 to 25% in another embodiment. Those skilled in the art will readilybe able to determine the exact amount of edible acid to include in thecoating solution, depending upon the pKa of the particular edible acidand the desired delay in dissolution of the enteric coating. Afterapplication of the enteric coating solution, as further described below,the percent of edible acid in the coating will range from about 10 toabout 80 weight % of the coating; 20 to 60% in one embodiment; and25-50% in another.

Enteric coatings can be obtained from a number of manufacturers, suchas, for example, Rohm Pharma GmbH of Darmstadt, Germany (EUDRAGIT).Particular blends of pH sensitive polymers and types can be selected byone of skill in the art. As an example, the manufacturer of EUDRAGITpolymers teaches that the EUDRAGIT grades for sustained releaseformulations are based on copolymers of acrylate and methacrylates withquaternary ammonium groups as functional groups as well as ethylacrylatemethylmethacrylate copolymers with a neutral ester group. EUDRAGITpolymers are available insoluble and/or permeable. For example, theEUDRAGIT RL-types are highly permeable, the EUDRAGIT RS-types are poorlypermeable, the EUDRAGIT NE-types are swellable and permeable. Therelease profiles and locations of release can be determined by varyingmixing ratios of the polymers and/or film thickness of the coatings andsuch profiles can be adjusted by those of skill in the art.

The amount of enteric coating is, in one embodiment about 0.1% of theformulation, such as the drug core, about 0.2% of the formulation, suchas the drug core, about 0.3% of the formulation, such as the drug core,about 0.4% of the formulation, such as the drug core, about 0.5% of theformulation, such as the drug core, about 0.6% of the formulation, suchas the drug core, about 0.7% of the formulation, such as the drug core,about 0.8% of the formulation, such as the drug core, about 0.9% of theformulation, such as the drug core, about 1% w/w of the formulation,such as the drug core; about 2%, w/w of the formulation, such as thedrug core, about 3%, w/w, of the formulation, such as the drug core,about 4%, w/w, of the formulation, such as the drug core; about 5% w/wof the formulation, such as the drug core; about 6%, w/w of theformulation, such as the drug core, about 7%, w/w, of the formulation,such as the drug core, about 8%, w/w, of the formulation, such as thedrug core; about 9% w/w of the formulation, such as the drug core; about10%, w/w of the formulation, such as the drug core, about 11%, w/w, ofthe formulation, such as the drug core, about 12%, w/w, of theformulation, such as the drug core; about 14% w/w of the formulation,such as the drug core; about 16%, w/w of the formulation, such as thedrug core, about 18%, w/w, of the formulation, such as the drug core,about 20%, w/w, of the formulation, such as the drug core; or more, ifdetermined to be appropriate. Seal coats may also be applied at amountsbetween about 1% and about 10% w/w of the formulation, such as the drugcore, between about 2% and 9% w/w of the formulation, such as the drugcore, between about 3% and 8% w/w of the formulation, such as the drugcore, between about 4% and 7% w/w of the formulation, such as the drugcore, between about 10% and 10% w/w of the formulation, such as the drugcore, and between about 5% and about 6% w/w of the formulation, such asthe drug core.

In some embodiments, coatings include those that selectively dissolve ata pH at or above the pH generally prevailing in the large intestine, forexample, above about pH 6, above about pH 6.2, above about pH 6.4, aboveabout pH 6.6, above about pH 6.8, or above about pH 7. In oneembodiment, the enteric coating will selectively dissolve in the pHrange of about 6.0 to about 7.5, in the pH range of about 6.2 to about7.5, in the pH range of about 6.4 to about 7.2, in the pH range of about6.5 to about 7, in the pH range of about 6.5 to 6.8. As an example ofcoatings and their “threshold” pH (the pH at which the coating willdissolve) which the skilled practitioner may consider include, but arenot limited to, cellulose phthalates (e.g., hydropropylmethylcellulosephthalates (HPMCPs)) that selectively dissolve at pH above 5.6, theEUDRAGIT family of polymers which are anionic polymer based onmethacrylic acid and methacrylates with carboxyl functional groups(e.g., EUDRAGIT L30D with threshold pH of 5.6, EUDRAGIT L with thresholdpH of 6.0, and EUDRAGIT S with threshold pH of 6.8), AQUATERIC withthreshold pH of 5.8, polyvinylacetate phthalate (PVAP) that releasesdrug at pH values above about 5.0, shellac that is obtained from a gummyexudation produced by female insects, Laccifer lacca ken, and releasesdrug at about pH 7.0, and cellulose acetate phthalate (CAP) withthreshold pH of 6.0. In a one embodiment, the drug is enteric-coatedwith EUDRAGIT S100 with threshold pH of 7.0, which will degrademeasurably at slightly lower pH such as pH 6.8.

In one embodiment, prior to application to the tablets, capsules, ordrug core of the present disclosure, the drug release controllingcomponent, such as, for example, the enteric coatings useful in thepresent disclosure, will be dissolved in a non-aqueous solution in orderto create the solid oral formulation of the present disclosure. Examplesof such non aqueous solutions include any known in the art suitable forpharmaceutical formulation procedures, including, for example,acetone-isopropanol solvent mixtures, methylene chloride-ethanol solventmixtures, acetone-ethanol solvent mixtures, benzene-methanol solventmixtures, acetate-ethanol solvent mixtures, among others. Proportions ofeach solvent to use and conditions will be readily determined by thoseof skill in the art. The solid dispersion of the composition of thepresent disclosure, in one embodiment, can be formed by spray dryingtechniques, although it will be understood that suitable soliddispersions may be formed by a skilled addressee utilizing otherconventional techniques, such as co-grinding, melt extrusion, freezedrying, rotary evaporation or any solvent removal process. In oneembodiment, spray drying is utilized. The enteric coating may be appliedover the entire surface area or portions thereof. In one embodiment, theentire surface area is coated.

In one embodiment, the enteric coat comprises EUDRAGIT S100 and theamount of enteric coat to use, relative to the drug core, or additionalto the drug core, an amount of about 0.1% of the drug core, about 0.2%of the drug core, about 0.3% of the drug core, about 0.4% of the drugcore, about 0.5% of the drug core, about 0.6% of the drug core, about0.7% of the drug core, about 0.8% of the drug core, about 0.9% of thedrug core, about 1% w/w of the drug core, about 2% w/w of the drug core;about 3% w/w of the drug core; about 4%, w/w of the drug core, about 5%w/w of the drug core; about 6%, w/w, of the drug core, about 7% w/w ofthe drug core, about 8%, w/w, of the drug core; about 9% w/w of the drugcore, about 10% w/w of the drug core; about 12%, w/w of the drug core;about 14%, w/w, of the drug core, about 16%, w/w/, of the drug core;about 18% w/w of the drug core; about 20%, w/w of the drug core, about22%, w/w, of the drug core, about 24%, w/w, of the drug core; about 26%w/w of the drug core; about 28%, w/w of the drug core, about 30%, w/w,of the drug core, about 32%, w/w, of the drug core; about 34% w/w of thedrug core; about 36%, w/w of the drug core, about 38%, w/w, of the drugcore, about 40%, w/w, of the drug core; about 42% w/w of the drug core;about 44%, w/w of the drug core; about 46%, w/w, of the drug core, about48%, w/w/, of the drug core; about 50% w/w of the drug core; about 52%,w/w of the drug core, about 54%, w/w, of the drug core, about 56%, w/w,of the drug core; about 58% w/w of the drug core; about 60%, w/w of thedrug core, about 62%, w/w, of the drug core, about 64%, w/w, of the drugcore; about 66% w/w of the drug core; about 68%, w/w of the drug core,about 70%, w/w, of the drug core, about 72%, w/w, of the drug core;about 74% w/w of the drug core; about 76%, w/w of the drug core; about78%, w/w, of the drug core, about 80%, w/w/, of the drug core; about 82%w/w of the drug core; about 84%, w/w of the drug core, about 86%, w/w,of the drug core, about 88%, w/w, of the drug core; about 90% w/w of thedrug core; about 92%, w/w of the drug core, about 91%, w/w, of the drugcore, about 96%, w/w, of the drug core; about 98%, w/w, of the drugcore, or more, if determined to be appropriate. Ranges include betweenabout 2% and about 20% w/w of the formulation; between about 3% andabout 15% w/w of the formulation; between about 4% and about 10% w/w ofthe formulation; between about 5% and about 9% w/w of the formulation;between about 6% and about 8% w/w of the formulation.

Administration

A composition containing a bile acid sequestrant (e.g., colesevelam) canbe administered to a mammal in any amount, at any frequency, and for anyduration effective to achieve a desired outcome (e.g., to treatdiarrhea). In some cases, a composition containing a bile acidsequestrant can be administered to a mammal to reduce colonic transit by10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55,60, 65, 70 percent or more). An effective amount of a compositioncontaining a bile acid sequestrant can be any amount that reduces amammal's diarrhea without producing significant toxicity to a mammalTypically, an effective amount of a composition containing a bile acidsequestrant can be any amount greater than or equal to about 200 mg of abile acid sequestrant (e.g., greater than or equal to about 200 mg,about 250 mg, about 500 mg, about 600 mg, about 650 mg, about 750 mg,about 1000 mg, about 1250 mg, about 1500 mg, about 1750 mg, about 2000mg, or more of, for example, colesevelam per administration) providedthat that amount does not induce significant toxicity to the mammal uponadministration. In some cases, an effective amount of a bile acidsequestrant, such as colesevelam, can be between 250 mg and 10 g (e.g.,between 250 mg and 1250 mg, between 500 mg and 1500 mg, or between 750mg and 2000 mg). Various factors can influence the actual effectiveamount used for a particular application. For example, the frequency ofadministration, duration of treatment, use of multiple treatment agents,route of administration, and severity of the diarrhea may require anincrease or decrease in the actual effective amount administered.

The frequency of administration of a composition containing a bile acidsequestrant can be any frequency that reduces a mammal's diarrheawithout producing significant toxicity to the mammal. For example, thefrequency of administration can be from about three times a day to abouttwice a week (e.g., once a day). The frequency of administration canremain constant or can be variable during the duration of treatment. Forexample, a composition containing a bile acid sequestrant can beadministered daily, twice a day, three times a day, five days a week, orthree days a week. A composition containing a bile acid sequestrant canbe administered for five days, 10 days, three weeks, four weeks, eightweeks, 48 weeks, one year, 18 months, two years, three years, or fiveyears. A course of treatment can include rest periods. For example, acomposition containing a bile acid sequestrant can be administered forfive days followed by a ten-day rest period, and such a regimen can berepeated multiple times. As with the effective amount, various factorscan influence the actual frequency of administration used for aparticular application. For example, the effective amount, duration oftreatment, use of multiple treatment agents, route of administration,and severity of the diarrhea may require an increase or decrease inadministration frequency.

An effective duration for administering a composition containing a bileacid sequestrant can be any duration that reduces a mammal's diarrheawithout producing significant toxicity to the mammal. Thus, theeffective duration can vary from several days to several weeks, months,or years. In general, the effective duration for the treatment ofdiarrhea can range in duration from one day to several days to severalmonths. In some cases, an effective duration can be for as long as anindividual mammal is alive and suffering from diarrhea. Multiple factorscan influence the actual effective duration used for a particulartreatment. For example, an effective duration can vary with thefrequency of administration, effective amount, use of multiple treatmentagents, route of administration, and severity of the diarrhea.

Lubricant

In exemplary embodiments, the pharmaceutical composition of thedisclosure may include lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof and other tableting aids such a magnesium stearateand microcrystalline cellulose

The pharmaceutical compositions disclosed herein may also furthercomprise at least one lubricant, which facilitates preparation of soliddosage forms of the pharmaceutical composition. Non-limiting examples ofsuitable lubricants include magnesium stearate, calcium stearate, zincstearate, colloidal silicon dioxide, hydrogenated vegetable oils,sterotex, polyoxyethylene monostearate, polyethylene glycol, sodiumstearyl fumarate, sodium benzoate, sodium lauryl sulfate, magnesiumlauryl sulfate, and light mineral oil. In exemplary embodiments, thelubricant may be magnesium stearate.

In embodiments in which the lubricant is included in the pharmaceuticalcomposition, the amount of the lubricant may range from about 0.1% toabout 3% by weight of the pharmaceutical composition. In variousembodiments, the amount of the lubricant may range from about 0.1% toabout 4% w/w, from about 0.3% to about 3% w/w, from about 0.4% to about2% w/w, or from about 1% to about 3% w/w by weight of the pharmaceuticalcomposition. In exemplary embodiments, the amount of the lubricant maybe about 1% by weight of the pharmaceutical composition, such as thecore or total formulation. In exemplary embodiments, the lubricant maybe present at a concentration of about 0.1%, about 0.2%, about 0.3%,about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%,about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%of the formulation.

Disintegrants

Disintegrants are used to facilitate disintegration of the tablet,thereby increasing the erosion rate relative to the dissolution rate,and are generally starches, clays, celluloses, algins, gums, orcrosslinked polymers (e.g., crosslinked polyvinyl pyrrolidone). Fillersinclude, for example, materials such as silicon dioxide, titaniumdioxide, alumina, talc, kaolin, powdered cellulose, and microcrystallinecellulose, as well as soluble materials such as mannitol, urea, sucrose,lactose, lactose monohydrate, dextrose, sodium chloride, and sorbitol.Solubility-enhancers, including solubilizers per se, emulsifiers, andcomplexing agents (e.g., cyclodextrins), may also be advantageouslyincluded in the present formulations. Stabilizers, as well known in theart, are used to inhibit or retard drug decomposition reactions thatinclude, by way of example, oxidative reactions. In various embodiments,the amount of the disintegrant may range from about 0.1% to about 4%w/w, from about 0.3% to about 3% w/w, from about 0.4% to about 2% w/w,or from about 1% to about 3% w/w by weight of the pharmaceuticalcomposition. Disintegrants may be present in a concentration of, forexample, from about 0.25 wt. % to about 3 wt. %, 0.5 wt. % to about 2.0wt. %, from about 0.75% to about 1.5% w/w of the formulation. Inexemplary embodiments, the disintegrant may be present at aconcentration of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%,about 16%, about 17%, about 18%, about 19%, or about 20% of theformulation.

Coating

The pharmaceutical composition can be coated with one or more entericcoatings, seal coatings, film coatings, barrier coatings, compresscoatings, fast disintegrating coatings, or enzyme degradable coatings.

Delayed release generally refers to the delivery so that the release canbe accomplished at some generally predictable location in the lowerintestinal tract more distal to that which would have been accomplishedif there had been no delayed release alterations. A preferred method fordelay of release is coating. Any coatings should be applied to asufficient thickness such that the entire coating does not dissolve inthe gastrointestinal fluids at pH below about 5, but does dissolve at pHabout 5 and above. It is expected that any enteric coating in thepractice of the compositions and methods of the disclosure to achievedelivery to the lower gastrointestinal tract, such as the largeintestine and/or colon.

In some cases, the formulation disclosed herein is coated with a coatingmaterial, e.g., a sealant. In some embodiments, the coating material iswater soluble. In some embodiments, the coating material comprises apolymer, plasticizer, a pigment, or any combination thereof. In someembodiments, the coating material is a form of a film coating, e.g., aglossy film, a pH independent film coating, an aqueous film coating, adry powder film coating (e.g., complete dry powder film coating), or anycombination thereof. In some embodiments, the coating material is highlyadhesive. In some embodiments, the coating material provides low levelof water permeation. In some embodiments, the coating material providesoxygen barrier protection. In some embodiments, the coating materialallows immediate disintegration for fast release of drug actives. Insome embodiments, the coating material is pigmented, clear, or white. Insome embodiments, the coating material is clear. Exemplary coatingmaterials include, without limitation, polyvinyl alcohol (PVA),cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP),methacrylic acid copolymers, cellulose acetate trimellitate (CAT),hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose (HPMC), hydroxy propyl methyl cellulose acetatesuccinate (hypromellose acetate succinate), shellac, sodium alginate,and zein. In some embodiments, the coating material comprises or is PVA.In some embodiments, the coating material comprises or is HPMC. Anexemplary PVA-based coating material includes Opadry II. In someinstances, the coating material is about 1, 2, 3, 4, 5, 6, 7, 8, 9, or10% of the weight of the formulation.

In some instances, the coating material represent between about 1% andabout 15% of the total weight of each first particulate, including, butnot limited to, between about 5% and about 10%, between about 6% andabout 10%, between about 7% and about 10%, between about 8% and about10%, or between about 9% and about 10% of the formulation. In someinstances, the coating material is greater than about 2%, greater thanabout 3%, greater than about 4%, greater than about 5%, greater thanabout 6%, greater than about 7%, greater than about 8%, greater thanabout 9%, or greater than about 10% of the weight of the formulation. Insome instances, the coating material is less than about 2%, less thanabout 3%, less than about 4%, less than about 5%, less than about 6%,less than about 7%, less than about 8%, less than about 9%, or less thanabout 10% of the weight of the formulation. In exemplary embodiments,the coating may be present at a concentration of about 0.1% of the drugcore, about 0.2% of the drug core, about 0.3% of the drug core, about0.4% of the drug core, about 0.5% of the drug core, about 0.6% of thedrug core, about 0.7% of the drug core, about 0.8% of the drug core,about 0.9% of the drug core, about 1% w/w of the drug core, about 2% w/wof the drug core; about 3% w/w of the drug core; about 4%, w/w of thedrug core, about 5% w/w of the drug core; about 6%, w/w, of the drugcore, about 7% w/w of the drug core, about 8%, w/w, of the drug core;about 9% w/w of the drug core, about 10% w/w of the drug core; about12%, w/w of the drug core; about 14%, w/w, of the drug core, about 16%,w/w/, of the drug core; about 18% w/w of the drug core; about 20%, w/wof the drug core, about 22%, w/w, of the drug core, about 24%, w/w, ofthe drug core; about 26% w/w of the drug core; about 28%, w/w of thedrug core, about 30%, w/w, of the drug core, about 32%, w/w, of the drugcore; about 34% w/w of the drug core; about 36%, w/w of the drug core,about 38%, w/w, of the drug core, about 40%, w/w, of the drug core;about 42% w/w of the drug core; about 44%, w/w of the drug core; about46%, w/w, of the drug core, about 48%, w/w/, of the drug core; about 50%w/w of the drug core; about 52%, w/w of the drug core, about 54%, w/w,of the drug core, about 56%, w/w, of the drug core; about 58% w/w of thedrug core; about 60%, w/w of the drug core, about 62%, w/w, of the drugcore, about 64%, w/w, of the drug core; about 66% w/w of the drug core;about 68%, w/w of the drug core, about 70%, w/w, of the drug core, about72%, w/w, of the drug core; about 74% w/w of the drug core; about 76%,w/w of the drug core; about 78%, w/w, of the drug core, about 80%, w/w/,of the drug core; about 82% w/w of the drug core; about 84%, w/w of thedrug core, about 86%, w/w, of the drug core, about 88%, w/w, of the drugcore; about 90% w/w of the drug core; about 92%, w/w of the drug core,about 91%, w/w, of the drug core, about 96%, w/w, of the drug core;about 98%, w/w, of the drug core, or more, if determined to beappropriate. Ranges include between about 2% and about 20% w/w of theformulation; between about 3% and about 15% w/w of the formulation;between about 4% and about 10% w/w of the formulation; between about 5%and about 9% w/w of the formulation; between about 6% and about 8% w/wof the formulation.

The compositions of the disclosure can be coated with one or moreenteric coatings, seal coatings, film coatings, barrier coatings,compress coatings, fast disintegrating coatings, or enzyme degradablecoatings. Multiple coatings can be applied for desired performance.Further, the dosage form can be designed for immediate release,pulsatile release, controlled release, extended release, delayedrelease, targeted release, synchronized release, or targeted delayedrelease. For release control, solid carriers can be made of variouscomponent types and levels or thicknesses of coats, with or without anactive ingredient. Such diverse solid carriers can be blended in adosage form to achieve a desired performance. The definitions of theseterms are known to those skilled in the art. In addition, the dosageform release profile can be affected by a polymeric matrix composition,a coated matrix composition, a multiparticulate composition, a coatedmultiparticulate composition, an ion-exchange resin-based composition,an osmosis-based composition, or a biodegradable polymeric composition.Without wishing to be bound by theory, it is believed that the releasemay be effected through favorable diffusion, dissolution, erosion,ion-exchange, osmosis or combinations thereof.

When formulated as a capsule, the capsule can be a hard or soft gelatincapsule, a starch capsule, or a cellulosic capsule. Although not limitedto capsules, such dosage forms can further be coated with, for example,a seal coating, an enteric coating, an extended release coating, or atargeted delayed release coating. These various coatings are known inthe art, but for clarity, the following brief descriptions are provided:seal coating, or coating with isolation layers: Thin layers of up to 20microns in thickness can be applied for variety of reasons, includingfor particle porosity reduction, to reduce dust, for chemicalprotection, to mask taste, to reduce odor, to minimize gastrointestinalirritation, etc. The isolating effect is proportional to the thicknessof the coating. Water soluble cellulose ethers are preferred for thisapplication. HPMC and ethyl cellulose in combination, or EUDRAGIT® E100,may be particularly suitable for taste masking applications. Traditionalenteric coating materials listed elsewhere can also be applied to forman isolating layer.

Extended or delayed release coatings are designed to effect deliveryover an extended period of time. The extended or delayed release coatingis a pH-independent coating formed of, for example, ethyl cellulose,hydroxypropyl cellulose, methylcellulose, hydroxymethyl cellulose,hydroxyethyl cellulose, acrylic esters, or sodium carboxymethylcellulose. Various extended or delayed release dosage forms can bereadily designed by one skilled in art to achieve delivery to both thesmall and large intestines, to only the small intestine, or to only thelarge intestine, depending upon the choice of coating materials and/orcoating thickness.

Enteric coatings are mixtures of acceptable excipients which are appliedto, combined with, mixed with or otherwise added to the carrier orcomposition. The coating may be applied to a compressed or molded orextruded tablet, a gelatin capsule, and/or pellets, beads, granules orparticles of the carrier or composition. The coating may be appliedthrough an aqueous dispersion or after dissolving in appropriatesolvent.

Dosage forms of the compositions of the present disclosure can also beformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a composition as described herein which utilizesan enteric coating to affect release in the lower gastrointestinaltract. The enteric coated dosage form may be a compressed or molded orextruded tablet/mold (coated or uncoated) containing granules, pellets,beads or particles of the active ingredient and/or other compositioncomponents, which are themselves coated or uncoated. The enteric coatedoral dosage form may also be a capsule (coated or uncoated) containingpellets, beads or granules of the solid carrier or the composition,which are themselves coated or uncoated.

Delayed release coating compositions comprise a polymeric material,e.g., cellulose butyrate phthalate, cellulose hydrogen phthalate,cellulose proprionate phthalate, polyvinyl acetate phthalate, celluloseacetate phthalate, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetate,dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose,hydroxypropyl methylcellulose acetate succinate, polymers and copolymersformed from acrylic acid, methacrylic acid, and/or esters thereof.Preferred enteric coatings herein are comprised of methacrylic acidcopolymers, types A, B, or C, which are commercially available from RohmTech, Inc. (Malden, Mass.), and water-based dispersions of celluloseacetate phthalate latex, which is commercially available from EastmanFine Chemicals (Kingsport, Tenn.).

Plasticizers can also be included in the tablets to modify theproperties and characteristics of the polymers used in the coats or coreof the tablets. As used herein, the term “plasticizer” includes allcompounds capable of plasticizing or softening a polymer or binder usedin compositions and methods of the disclosure. The plasticizer should beable to lower the melting temperature or glass transition temperature(softening point temperature) of the polymer or binder. Plasticizers,such as low molecular weight PEG, generally broaden the averagemolecular weight of a polymer in which they are included therebylowering its glass transition temperature or softening point.Plasticizers also generally reduce the viscosity of a polymer. It ispossible the plasticizer will impart some particularly advantageousphysical properties to the osmotic device of the disclosure.

Plasticizers useful in the compositions and methods of the disclosurecan include, by way of example and without limitation, low molecularweight polymers, oligomers, copolymers, oils, small organic molecules,low molecular weight polyols having aliphatic hydroxyls, ester-typeplasticizers, glycol ethers, poly(propylene glycol), multi-blockpolymers, single block polymers, low molecular weight poly(ethyleneglycol), citrate ester-type plasticizers, triacetin, propylene glycoland glycerin. Such plasticizers can also include ethylene glycol,1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethyleneglycol, triethylene glycol, tetraethylene glycol and other poly(ethyleneglycol) compounds, monopropylene glycol monoisopropyl ether, propyleneglycol monoethyl ether, ethylene glycol monoethyl ether, diethyleneglycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate,ethyl glycolate, dibutylsebacate, acetyltributylcitrate, triethylcitrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate.All such plasticizers are commercially available from sources such asAldrich or Sigma Chemical Co. It is also contemplated and within thescope of the disclosure, that a combination of plasticizers may be usedin the present formulation. The PEG based plasticizers are availablecommercially or can be made by a variety of methods, such as disclosedin Poly(ethylene glycol) Chemistry: Biotechnical and BiomedicalApplications (J. M. Harris, Ed.; Plenum Press, NY) the disclosure ofwhich is hereby incorporated by reference.

In certain embodiments, the plasticizer is present in a concentration ofabout 0.5% to about 2% w/w of the outer coating. In certain embodiments,the plasticizer is present in a concentration of about 0.75% to about 1%w/w of the outer coating. In certain embodiments, the plasticizer ispresent in a concentration of about 0.87% w/w of the outer coating.

The external coat can be applied as a compression coating, but it isgenerally applied as a sprayed coating. The sprayed coating is thinnerand lighter than the compression coating, and an osmotic deviceincluding the sprayed on external coating is, therefore, smaller than asimilar osmotic device having a compression coat. Moreover, the use of asprayed-on drug-containing water soluble coating permits the loading ofhigher amounts of drug than the use of a compression-coateddrug-containing water soluble coating. A smaller size osmotic devicegenerally results in increased patient compliance in taking the osmoticdevice and is therefore advantageous.

The tablets of the disclosure can be coated with a finish coat as iscommonly done in the art to provide the desired shine, color, taste orother aesthetic characteristics. Materials suitable for preparing thefinish coat are well known in the art and found in the disclosures ofmany of the references cited and incorporated by reference herein.

Multiple coatings can be applied for desired performance. Further, thedosage form can be designed for immediate release, pulsatile release,controlled release, extended release, delayed release, targeted release,synchronized release, or targeted delayed release. Forrelease/absorption control, solid carriers can be made of variouscomponent types and levels or thicknesses of coats, with or without anactive ingredient. Such diverse solid carriers can be blended in adosage form to achieve a desired performance. The definitions of theseterms are known to those skilled in the art. In addition, the dosageform release profile can be affected by a polymeric matrix composition,a coated matrix composition, a multiparticulate composition, a coatedmultiparticulate composition, an ion-exchange resin-based composition,an osmosis-based composition, or a biodegradable polymeric composition.Without wishing to be bound by theory, it is believed that the releasemay be effected through favorable diffusion, dissolution, erosion,ion-exchange, osmosis or combinations thereof.

Dosage forms of the compositions and methods of the disclosure canfurther be coated with, for example, a seal coating, an enteric coating,an extended release coating, or a targeted delayed release coating.These various coatings are known in the art, but for clarity, thefollowing brief descriptions are provided: seal coating, or coating withisolation layers: Thin layers of up to 20 microns in thickness can beapplied for variety of reasons, including for particle porosityreduction, to reduce dust, for chemical protection, to mask taste, toreduce odor, to minimize gastrointestinal irritation, etc. The isolatingeffect is proportional to the thickness of the coating. Water solublecellulose ethers are preferred for this application. HPMC and ethylcellulose in combination, or Eudragit E100, may be particularlysuitable. In exemplary embodiments, the coating may be OPADRY® Y-1-7000,a coating ready mix from Colorcon. Opadry Y-1-7000 contains hypromellose5 cP, titanium dioxide and macrogol/PEG 400; Shin-Etsu AQOAT®(hypromellose acetate succinate); COLORCOAT® FC4S which is Hydroxypropylmethyl cellulose. Traditional enteric coating materials listed elsewherecan also be applied to form an isolating layer.

Optionally, the sustained-release matrix multiparticulate systems,tablets, or capsules can be coated with a sustained release coating suchas the sustained release coatings described herein. Such coatingspreferably include a sufficient amount of hydrophobic and/or hydrophilicsustained-release material to obtain a weight gain level from about 2 toabout 25 percent, although the overcoat may be greater depending upon,e.g., the desired release rate. In certain embodiments, a sustainedrelease coating is applied to the sustained release spheroids, granules,or matrix multiparticulates. In such embodiments, the sustained-releasecoating may include a water insoluble material such as (a) a wax, eitheralone or in admixture with a fatty alcohol; or (b) shellac or zein. Thecoating is preferably derived from an aqueous dispersion of thehydrophobic sustained release material.

In other preferred embodiments of the present compositions and methodsof the disclosure, the sustained release material comprising thesustained-release coating is a pharmaceutically acceptable acrylicpolymer, including but not limited to acrylic acid and methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates,cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamide copolymer, poly(methyl methacrylate),polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers Ammonio methacrylatecopolymers are well known in the art as fully polymerized copolymers ofacrylic and methacrylic acid esters with a low content of quaternaryammonium groups. In order to obtain a desirable dissolution profile, itmay be necessary to incorporate two or more ammonio methacrylatecopolymers having differing physical properties, such as different molarratios of the quaternary ammonium groups to the neutral (meth)acrylicesters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings which may be used in accordance with the presentdisclosure. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit® from Rohm GMBH andCo. Kg Darmstadt, Germany. There are several different types ofEudragit®. For example, Eudragit E is an example of a methacrylic acidcopolymer which swells and dissolves in acidic media. Eudragit L is amethacrylic acid copolymer which does not swell at about pH<5.7 and issoluble at about pH>6. Eudragit S does not swell at about pH<6.5 and issoluble at about pH>7. Eudragit RL and Eudragit RS are water swellable,and the amount of water absorbed by these polymers is pH-dependent;however, dosage forms coated with Eudragit RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available under theTradenames Eudragit® RL30D and Eudragit® RS30D, respectively. Eudragit®RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylicesters with a low content of quaternary ammonium groups, the molar ratioof ammonium groups to the remaining neutral (meth)acrylic esters being1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D. The mean molecularweight is about 150,000. The code designations RL (high permeability)and RS (low permeability) refer to the permeability properties of theseagents. Eudragit® RL/RS mixtures are insoluble in water and in digestivefluids. However, coatings formed from the same are swellable andpermeable in aqueous solutions and digestive fluids.

Examples of suitable plasticizers include water insoluble plasticizerssuch as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributylcitrate, and triacetin, acetylated monoglycerides, diacylatedmonoglyceride, phthalate esters, castor oil, and combinations thereof,etc. may be used. Acetylated monoglycerides is an especially preferredplasticizer for the disclosure.

Extended release coatings are designed to effect delivery over anextended period of time. The extended release coating is apH-independent coating formed of, for example, ethyl cellulose,hydroxypropyl cellulose, methylcellulose, hydroxymethyl cellulose,hydroxyethyl cellulose, acrylic esters, or sodium carboxymethylcellulose. Various extended release dosage forms can be readily designedby one skilled in art to achieve delivery to both the small and largeintestines, to only the small intestine, or to only the large intestine,depending upon the choice of coating materials and/or coating thickness.

Enteric coatings are mixtures of pharmaceutically acceptable excipientswhich are applied to, combined with, mixed with or otherwise added tothe carrier or composition. The coating may be applied to a compressedor molded or extruded tablet, a gelatin capsule, and/or pellets, beads,granules or particles of the carrier or composition. The coating may beapplied through an aqueous dispersion or after dissolving in appropriatesolvent.

In certain embodiments, the pharmaceutical composition, upon oraladministration to a human or non-human patient in need thereof, providescontrolled release for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 14, 16, 18, 20, 24, 36, 48, 72, 96, 120, 144, or 168 hours.

The term “sustained release” refers release of a drug from its dosageform (e.g., tablet) at such a rate that its blood levels are maintainedwithin the therapeutic range (i.e., at or above minimum effectiveconcentration (MEC)) but below toxic levels over an extended period oftime (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20,22, 24, 36, 48, 72, 96, 120, 144, or 168 hours or greater). The term“sustained release” may be used interchangeably with “slow-release,”“controlled release,” or “extended release.” The sustained releaseproperty of a dosage form is typically measured by an in vitrodissolution method and confirmed by an in vivo blood concentration-timeprofile (i.e., a pharmacokinetic profile).

In certain embodiments, the pharmaceutical compositions of the presentdisclosure release about 90% to 100% of their pharmaceutically activeagents in a linear or near linear fashion for at least about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 36, 48, 72, 96, 120, 144, or 168 hours in an in vitro dissolutionanalysis.

Delayed release generally refers to the delivery so that the release canbe accomplished at some generally predictable location in the lowerintestinal tract more distal to that which would have been accomplishedif there had been no delayed release alterations. The preferred methodfor delay of release is coating. Any coatings should be applied to asufficient thickness such that the entire coating does not dissolve inthe gastrointestinal fluids at pH below about 5, but does dissolve at pHabout 5 and above. It is expected that any anionic polymer exhibiting apH-dependent solubility profile can be used as an enteric coating in thepractice of the present disclosure to achieve delivery to the lowergastrointestinal tract. Polymers for use in the present disclosure areanionic carboxylic polymers.

In exemplary embodiments, the coating may comprise shellac, also calledpurified lac, a refined product obtained from the, resinous secretion ofan insect. This coating dissolves in media of pH>7.

Colorants, detackifiers, surfactants, antifoaming agents, lubricants,stabilizers such as hydroxy propyl cellulose, acid/base may be added tothe coatings besides plasticizers to solubilize or disperse the coatingmaterial, and to improve coating performance and the coated product.

Dosage Forms

The compositions of the present disclosure can provided in the form of aminicapsule, a capsule, a tablet, an implant, a troche, a lozenge(minitablet), a temporary or permanent suspension, an ovule, asuppository, a wafer, a chewable tablet, a quick or fast dissolvingtablet, an effervescent tablet, a granule, a film, a sprinkle, a pellet,a bead, a pill, a powder, a triturate, a platelet, a strip or a sachet.Compositions can also be administered after being mixed with, forexample yoghurt or fruit juice and swallowed or followed with a drink orbeverage. These forms are well known in the art and are packagedappropriately. The compositions can be formulated for oral or rectaldelivery.

Tablets prepared for oral administration according to the disclosure,and manufactured using direct compression, will generally contain otherinactive additives such as binders, lubricants, disintegrants, fillers,stabilizers, surfactants, coloring agents, and the like. Binders areused to impart cohesive qualities to a tablet, and thus ensure that thetablet remains intact after compression. Suitable binder materialsinclude, but are not limited to, starch (including corn starch andpregelatinized starch), gelatin, sugars (including sucrose, glucose,dextrose and lactose), polyethylene glycol, waxes, and natural andsynthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone,cellulosic polymers (including hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, microcrystalline cellulose, ethylcellulose, hydroxyethyl cellulose, and the like), and Veegum. Lubricantsare used to facilitate tablet manufacture, promoting powder flow andpreventing particle capping (i.e., particle breakage) when pressure isrelieved. Useful lubricants are magnesium stearate ( ) calcium stearate,stearic acid, and hydrogenated vegetable oil (preferably comprised ofhydrogenated and refined triglycerides of stearic and palmitic acids atabout 1 wt. % to 5 wt. %, most preferably less than about 2 wt. %).Lubricants may be present in a concentration of, for example, from about0.25 wt. % to about 3 wt. %, 0.5 wt. % to about 2.0 wt. %, from about0.75% to about 1.5%.

Disintegrants are used to facilitate disintegration of the tablet,thereby increasing the erosion rate relative to the dissolution rate,and are generally starches, clays, celluloses, algins, gums, orcrosslinked polymers (e.g., crosslinked polyvinyl pyrrolidone). Fillersinclude, for example, materials such as silicon dioxide, titaniumdioxide, alumina, talc, kaolin, powdered cellulose, and microcrystallinecellulose, as well as soluble materials such as mannitol, urea, sucrose,lactose, lactose monohydrate, dextrose, sodium chloride, and sorbitol.Solubility-enhancers, including solubilizers per se, emulsifiers, andcomplexing agents (e.g., cyclodextrins), may also be advantageouslyincluded in the present formulations. Stabilizers, as well known in theart, are used to inhibit or retard drug decomposition reactions thatinclude, by way of example, oxidative reactions. Disintegrants may bepresent in a concentration of, for example, from about 0.25 wt. % toabout 3 wt. %, 0.5 wt. % to about 2.0 wt. %, from about 0.75% to about1.5%.

Shellac, also called purified lac, a refined product obtained from the,resinous secretion of an insect. This coating dissolves in media ofpH>7.

Colorants, detackifiers, surfactants, antifoaming agents, lubricants,stabilizers such as hydroxy propyl cellulose, acid/base may be added tothe coatings besides plasticizers to solubilize or disperse the coatingmaterial, and to improve coating performance and the coated product.

In carrying out the method of the present disclosure, the combination ofthe disclosure may be administered to mammalian species, such as dogs,cats, humans, etc. and as such may be incorporated in a conventionalsystemic dosage form, such as a tablet, capsule, or elixir. The abovedosage forms will also include the necessary carrier material,excipient, lubricant, buffer, antibacterial, bulking agent (such asmannitol), anti-oxidants (ascorbic acid of sodium bisulfate) or thelike.

The dose administered may be carefully adjusted according to age, weightand condition of the patient, as well as the route of administration,dosage form and regimen and the desired result.

The compositions of the disclosure may be administered in the dosageforms in single or divided doses of one to four times daily, or may beadministered multiple times per day. It may be advisable to start apatient on a low dose combination and work up gradually to a high dosecombination.

Tablets of various sizes can be prepared, e.g., of about 2 to 2000 mg intotal weight, containing one or both of the active ingredients, with theremainder being a physiologically acceptable carrier of other materialsaccording to accepted practice. Gelatin capsules can be similarlyformulated.

Liquid formulations can also be prepared by dissolving or suspending oneor the combination of active substances in a conventional liquid vehicleacceptable for administration so as to provide the desired dosage in,for example, one to four teaspoonfuls.

Dosage forms can be administered to the patient on a regimen of, forexample, one, two, three, four, five, six, or other multiple doses perday.

In order to more finely regulate the dosage schedule, the activesubstances may be administered separately in individual dosage units atthe same time or carefully coordinated times. The respective substancescan be individually formulated in separate unit dosage forms in a mannersimilar to that described above.

In formulating the compositions, the active substances, in the amountsdescribed above, may be compounded according to accepted practice with aphysiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, flavor, etc., in the particular type of unitdosage form.

Packaging/Treatment Kits

The present disclosure relates to a kit for conveniently and effectivelycarrying out the methods in accordance with the present disclosure. Suchkits may be suited for the delivery of solid oral forms such as tabletsor capsules. Such a kit may include a number of unit dosages. Such kitscan include a means for containing the dosages oriented in the order oftheir intended use. An example of a means for containing the dosages inthe order of their intended uses is a card. An example of such a kit isa “blister pack”. Blister packs are well known in the packaging industryand are widely used for packaging unit dosage forms. If desired, theblister can be in the form of a childproof blister, i.e. a blister thatis difficult for a child to open, yet can be readily opened by an adult.If desired, a memory aid can be provided, for example in the form ofnumbers, letters, or other markings or with a calendar feature and/orcalendar insert, designating the days and the sections of a day in thetreatment schedule in which the dosages can be administered, such as,for example, an AM dose is packaged with a “midday” and a PM dose; or anAM dose is packaged with a PM dose. Alternatively, placebo dosages, orvitamin or dietary supplements, either in a form similar to or distinctfrom the active dosages, can be included.

The disclosure provides compositions, including preparations,formulations and/or kits, comprising combinations of ingredients, asdescribed above (including the multi-ingredient combinations of drugs ofthe disclosure), that are serviceable as therapies for treating,preventing or improving conditions, states and disease as provided inthe disclosure. In one aspect, each member of the combination ofingredients is manufactured in a separate package, kit or container; or,all or a subset of the combinations of ingredients are manufactured in aseparate package or container. In alternative aspects, the package, kitor container comprises a blister package, a clamshell, a tray, a shrinkwrap and the like.

In one aspect, the package, kit or container comprises a “blisterpackage” (also called a blister pack, or bubble pack). In one aspect,the blister package consists two or more separate compartments. Thisblister package is made up of two separate material elements: atransparent plastic cavity shaped to the product and its blister boardbacking. These two elements are then joined together with a heat sealingprocess which allows the product to be hung or displayed. Exemplarytypes of “blister packages” include: Face seal blister packages, gangrun blister packages, mock blister packages, interactive blisterpackages, slide blister packages.

Blister packs, clamshells or trays are forms of packaging used forgoods; thus, the disclosure provides for blister packs, clamshells ortrays comprising a composition (e.g., a (the multi-ingredientcombination of drugs of the disclosure) combination of activeingredients) of the disclosure. Blister packs, clamshells or trays canbe designed to be non-reclosable, so consumers can tell if a package hasalready opened. They are used to package for sale goods where producttampering is a consideration, such as the agents of the disclosure. Inone aspect, a blister pack of the disclosure comprises a moulded PVCbase, with raised areas (the “blisters”) to contain the tablets, pills,etc. comprising the combinations of the disclosure, covered by a foillaminate. Tablets, pills, etc. are removed from the pack either bypeeling the foil back or by pushing the blister to force the tablet tobreak the foil. In one aspect, a specialized form of a blister pack is astrip pack.

In one aspect, a blister pack also comprises a method of packaging wherethe compositions comprising combinations of ingredients of thedisclosure are contained in-between a card and clear PVC. The PVC can betransparent so the item (pill, tablet, geltab, etc.) can be seen andexamined easily; and in one aspect, can be vacuum-formed around a mouldso it can contain the item snugly and have room to be opened uponpurchase. In one aspect, the card is brightly colored and designeddepending on the item (pill, tablet, geltab, etc.) inside, and the PVCis affixed to the card using pre-formed tabs where the adhesive isplaced. The adhesive can be strong enough so that the pack may hang on apeg, but weak enough so that this way one can tear open the join andaccess the item. Sometimes with large items or multiple enclosed pills,tablets, geltabs, etc., the card has a perforated window for access. Inone aspect, more secure blister packs, e.g., for items such as pills,tablets, geltabs, etc. of the disclosure are used, and they can compriseof two vacuum-formed PVC sheets meshed together at the edges, with theinformative card inside.

In one aspect, blister packaging comprises at least two components(e.g., is a multi-ingredient combination of drugs of the disclosure): athermoformed “blister” which houses the product (e.g., a combination ofthe disclosure), and then a “blister card” that is a printed card withan adhesive coating on the front surface. During the assembly process,the blister component, which is most commonly made out of PVC, isattached to the blister card using a blister machine. Conventionalblister packs can also be sealed.

As discussed herein, the products of manufacture of the disclosure cancomprise the packaging of the therapeutic drug combinations of thedisclosure, alone or in combination, as “blister packages” or as aplurality of packettes, including as lidded blister packages, liddedblister or blister card or packets, or a shrink wrap.

In one aspect, any of the disclosure's products of manufacture,including kits or blister packs, include memory aids to help remindpatients when and how to take the agents of the disclosure.

The treatment kits can be constructed in a variety of forms familiar toone of ordinary skill in the art. The kits comprise at least one unitdosage of an active for administration according to a daily regimen anda means for containing the unit dosages. The treatment kits can, forexample, be constructed for administration once daily, twice daily,thrice daily, four times daily, multiple administrations daily, or otherdosage regimens. The kits comprise a means for the daily administrationof an agent of the disclosure. In one embodiment the kits include fromabout one to about four unit dosages.

In one embodiment, the means for containing the unit dosages is a card,including, for example, a card that is capable of being folded. Thiscard will be referred to herein as a main card, or alternatively aprincipal card or a first card, to distinguish it from additionaloptional cards, circulars, or other such materials which can beassociated with the kit. This main card can be folded with a simplecrease, or alternatively, with a double crease, so as to exhibit aspine, similar to the spine of a closed book. The main card can comprisea printable surface, i.e. a surface upon which the product name,appropriate administration instructions, product information, drawings,logos, memory aids, calendar features, etc. can be printed. The maincard can comprise a means for containing said unit dosage or differentdosages designated for different time of the day, and a memory aid foradministering said unit dosage or dosages. The main card, especially ifit is prepared from two or more laminated paperboard surfaces, cancomprise a slit or pocket, for example in one of the inner paperboardsurfaces of the folded card. The slit or pocket can be used to contain aremovable secondary card, i.e. a second card or insert card, which isnot permanently attached or affixed to the main card.

The memory aid can include a listing of the days of the week, i.e.Sunday, Monday, Tuesday, Wednesday, Thursday, Friday, and Saturday, withappropriate spaces for the patient to select and indicate on the cardthe preferred day of the week on which to administer the therapy. Thememory aid can include a listing of the time of day with appropriatespaces for the patient to select and indicate on the card the preferredtime of day (e.g.: AM, PM, midday) at which to administer the therapy.The memory aid can also include removable stickers having an appropriatepressure sensitive adhesive to facilitate easy removal and refasteningto a desired surface such as a calendar or dayminder. The removablestickers can be located on the main card, or can be located on thesecondary card which is constructed so that it can be readily insertedinto and removed from the optional slit in the main card. Additionally,the optional slit can contain additional patient information and othercirculars.

Other means for containing said unit dosages can include bottles andvials, wherein the bottle or vial comprises a memory aid, such as aprinted label for administering said unit dosage or dosages. The labelcan also contain removable reminder stickers for placement on a calendaror dayminder to further help the patient to remember when to take adosage or when a dosage has been taken.

The disclosure will be illustrated in more detail with reference to thefollowing Examples, but it should be understood that the presentdisclosure is not deemed to be limited thereto.

EXAMPLES Example 1

Colesevalam Hydrochloride Tablet 625 mg

Ingredient Qty/mg % w/w Colesevelam hydrochloride 625 63.13 anhydrousMicrocrystalline cellulose (Avicel 220 22.22 pH101) Hydroxy propylmethylcellulose 20 2 (HPMC E5LV) Hydroxy propyl methylcellulose 100 10.1(K4M) Colloidal silicon dioxide 15 1.5 Magnesium stearate 10 1 Coretablet weight 990 100 Coating Hydroxypropyl methylcellulose 69.8 6.53(HPMC E50SLV) Diacylated monoglyceride 9.4 0.88 water q.s. Coated tablettotal weight 1069.2 100

Example 2

Colesevalam Hydrochloride Tablet 500 mg

Ingredient Qty/mg % w/w Colesevelam hydrochloride 500 57.8 anhydrousMicrocrystalline cellulose (Avicel 220 25.4 pH101) Hydroxy propylmethylcellulose 20 2.31 (HPMC E5LV) Hydroxy propyl methylcellulose 10011.56 (K4M) Colloidal silicon dioxide 15 1.7 Magnesium stearate 10 1.16Core tablet weight 865 100 Coating Hydroxypropyl methylcellulose 69.87.4 (HPMC E50SLV) Diacylated monoglyceride 9.4 1 Water q.s. Coatedtablet total weight 944.2 100

Example 3

Colesevalam Hydrochloride Tablet 250 mg

Ingredient Qty/mg % w/w Colesevelam hydrochloride 250 40.65 anhydrousMicrocrystalline cellulose (Avicel 220 35.77 pH101) Hydroxy propylmethylcellulose 20 3.25 (HPMC E5LV) Hydroxy propyl methylcellulose 10016.26 (K4M) Colloidal silicon dioxide 15 2.44 Magnesium stearate 10 1.6Core tablet weight 615 100 Coating Hydroxypropyl methylcellulose 69.810.05 (HPMC E50SLV) Diacylated monoglyceride 9.4 1.35 Water q.s. Coatedtablet total weight 694.2 100

Example 4

Colesevalam Hydrochloride Tablet 250 mg

Ingredients Qty/mg % w/w 1. Colesevalam Hydrochloride anhydrous 250 57.52. Microcrystalline cellulose (Avicel pH101) 110 25.28 3. Hydroxy propylmethylcellulose (HPMC E5LV) 10 2.29 4. Hydroxy propyl methylcellulose(K4M) 50 11.49 5. Colloidal silicon dioxide 10 2.29 6. Magnesiumstearate 5 1.15 7. Core tablet weight 435 Coating 8. Hydroxypropylmethylcellulose (HPMC 31.5 6.7 E50SLV) 9. Diacylated monoglyceride 3.50.74 Water q.s. 10. Coated tablet weight 470

Example 5

Colesevalam Hydrochloride Tablet 500 mg

Ingredients Qty/mg % w/w 1. Colesevalam Hydrochloride anhydrous 500 57.82. Microcrystalline cellulose (Avicel pH101) 220 25.43 3. Hydroxy propylmethylcellulose (HPMC E5LV) 20 2.31 4. Hydroxy propyl methylcellulose(K4M) 100 11.56 5. Colloidal silicon dioxide 15 1.73 6. Magnesiumstearate 10 1.16 7. Core tablet weight 865 Coating 8. Hydroxypropylmethylcellulose (HPMC 66.0 7.02 E50SLV) 9. Diacylated monoglyceride 9.00.96 Water q.s. 10. Coated tablet weight 940

Example 6

Colesevalam Hydrochloride Tablet 625 mg

Ingredients Qty/mg % w/w 1. Colesevalam Hydrochloride anhydrous 62563.13 2. Microcrystalline cellulose (Avicel pH101) 220 22.22 3. Hydroxypropyl methylcellulose (HPMC E5LV) 20 2.02 4. Hydroxy propylmethylcellulose (K4M) 100 10.10 5. Colloidal silicon dioxide 15 1.52 6.Magnesium stearate 10 1.01 7. Core tablet weight 990 Coating 8.Hydroxypropyl methylcellulose (HPMC 69.8 6.53 E50SLV) 9. Diacylatedmonoglyceride 9.4 0.88 Water q.s. 10. Coated tablet weight 1069.2

Example 7 Manufacturing Formula

Batch Size: 100000 Tablets

% w/w Qty./ S. mg/ per Batch No Ingredients tablet tablet in kg CoreTablet 1 Colesevalam Hydrochloride anhydrous 625 63.13 62.5 2Microcrystalline cellulose (Avicel pH101) 220 22.22 22.0 3 Hydroxypropyl methylcellulose (HPMC 20 2.02 2.0 E5LV) 4 Hydroxy propylmethylcellulose (K4M) 100 10.10 10.0 5 Colloidal silicon dioxide 15 1.511.5 6 Magnesium stearate 10 1.01 1.0 Core tablet weight 990 coating 7Hydroxypropyl methylcellulose (HPMC 69.80 6.52 6.98 E50SLV) 8 Diacylatedmonoglyceride 9.40 0.87 0.94 9 P water Q.S — Q.S Coated tablet weight1069.2 — —Manufacturing Process:1. Sift colesevelam hydrochloride Microcrystalline cellulose, HPMC ESLV(R), Hydroxypropyl methyl cellulose (K4M(R) and Aerosil R-200 through40imesh and mix for 10 minutes in bin blender. Sift Magnesium stearatethrough #60 mesh and add to the above blend and mix for another 5 min.2. The above lubricated blend is then compressed into tablets Coating ofTablets.3. Prepare coating solution by dissolving acetylated monoglyceride inpurified water under stirring followed addition of HPMC E50LV(R) intoit, under stirring until uniform dispersion formed.4. The coating solution of 3) is sprayed onto the core tablets of 2)using a Suitable coating machine to achieve a weight gain between 6-8%w/w per tablet.

While the disclosure has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. An oral drug delivery system comprising: a) acore comprising: a therapeutically effective amount of at least oneactive agent present in an amount of from about 50% to about 64% w/w ofthe core, wherein the at least one active agent is selected from thegroup consisting of colesevelam, pharmaceutically acceptable saltsthereof, and combinations thereof, and a drug release controllingcomponent capable of providing release of the at least one active agentprimarily in a region of a patient selected from the group consisting ofa lower gastrointestinal tract, a large intestine, a jejunum, a ileum, acecum, a colon, a rectum, and combinations thereof, wherein the drugrelease controlling component comprises low viscosity hydroxypropylmethyl cellulose (HPMC) and high viscosity HPMC, and comprises at leastone erodible matrix material selected from the group consisting ofhydroxypropyl methylcellulose phthalate (HPMCP),hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethyl cellulose acetate trimellitate (HPMCAT), ethylhydroxyethylcellulose (EHEC), and combinations thereof, wherein said at leastone erodible matrix material is present in a concentration of about 5%to about 15% w/w of the core; b) a barrier coating encasing the core,wherein said barrier coating comprises HPMC, and c) an enteric coatingon the barrier coating comprising hypromellose acetate succinate, andfurther comprising a plasticizer, wherein after ingestion by the patientthe at least one active agent is released primarily in the regionselected from the group consisting of the lower gastrointestinal tract,the large intestine, the jejunum, the ileum, the cecum, the colon, therectum, and combinations thereof.
 2. The system of claim 1, wherein theat least one active agent is present in an amount selected from thegroup consisting of about 250 mg, about 500 mg, about 625 mg, and about650 mg.
 3. The system of claim 1, wherein the at least one active agentis present in an amount of about 250 to about 650 mg.
 4. The system ofclaim 1, wherein the at least one active agent is present in an amountof about 63.13% w/w of the core.
 5. The system of claim 1, wherein theoral drug delivery system releases the at least one active agentprimarily in the lower gastrointestinal tract.
 6. The system of claim 1,wherein about 80% to about 100% w/w of the at least one active agent isreleased in the lower gastrointestinal tract.
 7. The system of claim 1,wherein about 100% w/w of the at least one active agent is released inthe lower gastrointestinal tract.
 8. The system of claim 1, wherein theoral drug delivery system releases the at least one active agentprimarily in the large intestine.
 9. The system of claim 1, whereinabout 80% to about 100% w/w of the at least one active agent is releasedin the large intestine.
 10. The system of claim 1, wherein about 100%w/w of the at least one active agent is released in the large intestine.11. The system of claim 1, wherein the oral drug delivery systemreleases the at least one active agent primarily in the colon.
 12. Thesystem of claim 1, wherein about 80% to about 100% w/w of the at leastone active agent is released in the colon.
 13. The system of claim 1,wherein about 100% w/w of the at least one active agent is released inthe colon.
 14. The system of claim 1, wherein the at least one erodiblematrix material is present in a concentration of about 8% to about 13%w/w of the core.
 15. The system of claim 1, wherein the at least oneerodible matrix material is present in a concentration of about 12.12%w/w of the core.
 16. The system of claim 1, wherein the core furthercomprises at least one excipient selected from the group consisting of:diluent, binding agent, lubricant, disintegrant, stabilizer, andcombinations thereof.
 17. The system of claim 1, wherein the corefurther comprises a disintegrant, wherein the disintegrant comprisescolloidal silicon dioxide, in an amount of from about 0.1% to about 4%w/w of the core.
 18. The system of claim 1, wherein the core furthercomprises a lubricant, wherein the lubricant comprises magnesiumstearate, in an amount of from about 0.1% to about 4% w/w of the core.19. The system of claim 1, wherein the enteric coating allows the atleast one active agent to pass through a stomach substantially intactand subsequently disintegrate primarily in the large intestine of thepatient.
 20. The system of claim 1, wherein the plasticizer is presentin a concentration of about 0.5% to about 2% w/w of the enteric coating.21. The system of claim 1, wherein the plasticizer is present in aconcentration of about 0.75% to about 1% w/w of the enteric coating. 22.The system of claim 1, wherein the plasticizer is present in aconcentration of about 0.87% w/w of the enteric coating.
 23. The systemof claim 1, wherein the plasticizer is selected from the groupconsisting of dibutyl sebacate, diethyl phthalate, triethyl citrate,tributyl citrate, triacetin, acetylated monoglycerides, diacylatedmonoglyceride, phthalate esters, castor oil, and combinations thereof.24. The system of claim 1, wherein the plasticizer is triethyl citrate.